Co-reporter:Shanshan Li, Bing Xiong, Yuan Xu, Tao Lu, Xiaomin Luo, Cheng Luo, Jingkang Shen, Kaixian Chen, Mingyue Zheng, and Hualiang Jiang
Journal of Chemical Theory and Computation 2014 Volume 10(Issue 6) pp:2255-2264
Publication Date(Web):May 12, 2014
DOI:10.1021/ct5002279
The C-terminal domain of the bacterial transcription antiterminator RfaH undergoes a dramatic all-α-helix to all-β-barrel transition when released from its N-terminal domain. These two distinct folding patterns correspond to different functions: the all-α state acts as an essential regulator of transcription to ensure RNA polymerase binding, whereas the all-β state operates as an activator of translation by interacting with the ribosomal protein S10 and recruits ribosomal mRNA. Accordingly, this drastic conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary functionally relevant structural transition, we constructed Markov state models using an adaptive seeding method. The constructed models highlight several parallel folding pathways with heterogeneous molecular mechanisms, which reveal the folding kinetics and atomic details of the conformational transition.
Co-reporter:Xun Ji, Chunmei Xia, Jiang Wang, Mingbo Su, Lei Zhang, Tiancheng Dong, Zeng Li, Xia Wan, Jingya Li, Jia Li, Linxiang Zhao, Zhaobing Gao, Hualiang Jiang, Hong Liu
European Journal of Medicinal Chemistry 2014 Volume 86() pp:242-256
Publication Date(Web):30 October 2014
DOI:10.1016/j.ejmech.2014.08.059
•The DPP4 inhibitory activities and selectivity of compounds 8 and 9 were tested.•Compounds 8l and 9l showed good efficacy in OGTTs in ICR mice.•Compound 9l reduced the blood glucose level in diabetic BKS db/db mice with multiple doses for 5 weeks.•Compounds 8l and 9l did not block hERG channel and displayed no inhibition of liver metabolic enzymes.Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.By rational design and modification, compound 9l showed excellent DPP4 inhibitory activity, good selectivity and efficacy in OGTTs in ICR mice, did not block the hERG channel and no inhibition of live metabolic enzyme like CYP2C9.
Co-reporter:Ping Li, Zhuxi Chen, Haiyan Xu, Haifeng Sun, Hao Li, Hong Liu, Huaiyu Yang, Zhaobing Gao, Hualiang Jiang and Min Li
Cell Research 2013 23(9) pp:1106-1118
Publication Date(Web):June 25, 2013
DOI:10.1038/cr.2013.82
Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.
Co-reporter:Xianjie Chen, Hui Chen, Xun Ji, Hualiang Jiang, Zhu-Jun Yao, and Hong Liu
Organic Letters 2013 Volume 15(Issue 8) pp:1846-1849
Publication Date(Web):April 5, 2013
DOI:10.1021/ol4004542
An asymmetric organo- and gold-catalyzed one-pot sequential Mannich/hydroamination reaction has been developed. Using this protocol, spiro[pyrrolidin-3,2′-oxindole] derivatives were synthesized in good yields (up to 91%) and excellent enantioselectivities (up to 97% ee).
Co-reporter:Lili Xu, Shanglin Zhou, Kunqian Yu, Bo Gao, Hualiang Jiang, Xuechu Zhen, and Wei Fu
Journal of Chemical Information and Modeling 2013 Volume 53(Issue 12) pp:3202-3211
Publication Date(Web):November 18, 2013
DOI:10.1021/ci400481p
The serotonin receptor subtype 1A (5-HT1AR) has been implicated in several neurological conditions, and potent 5-HT1AR agonists have therapeutic potential for the treatment of depression, anxiety, schizophrenia, and Parkinson’s disease. In the present study, a homology model of 5-HT1AR was built based on the latest released high-resolution crystal structure of the β2AR in its active state (PDB: 3SN6). A dynamic pharmacophore model, which takes the receptor flexibility into account, was constructed, validated, and applied to our dynamic pharmacophore-based virtual screening approach with the aim to identify potential 5-HT1AR agonists. The obtained hits were subjected to 5-HT1AR binding and functional assays, and 10 compounds with medium or high Ki and EC50 values were identified. Among them, FW01 (Ki = 51.9 nM, EC50 = 7 nM) was evaluated as the strongest agonist for 5-HT1AR. The active 5-HT1AR model and dynamic pharmacophore model obtained from this study can be used for future discovery and design of novel 5-HT1AR agonists. Also, by integrating all computational and available experimental data, a stepwise 5-HT1AR signal transduction model induced by agonist FW01 was proposed.
Co-reporter:Yunfeng Xie, Xianjie Chen, Jie Qin, Xiangqian Kong, Fei Ye, Yuren Jiang, Hong Liu, Hualiang Jiang, Ronen Marmorstein, Cheng Luo
Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 8) pp:2306-2312
Publication Date(Web):15 April 2013
DOI:10.1016/j.bmcl.2013.02.072
The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly occurs in about 8% of all human malignancies and about 50% of all melanomas. In this study, we employed virtual screening and chemical synthesis to identify a series of N-(thiophen-2-yl) benzamide derivatives as potent BRAFV600E inhibitors. Structure–activity relationship studies of these derivatives revealed that compounds b40 and b47 are the two most potent BRAFV600E inhibitors in this series.
Co-reporter:Jing Chen;Yechun Xu;Fang Bai;Qiufeng Liu;Xicheng Wang;Junfeng Gu;Honglin Li;Jianpeng Ma;José N. Onuchic
PNAS 2013 Volume 110 (Issue 11 ) pp:4273-4278
Publication Date(Web):2013-03-12
DOI:10.1073/pnas.1301814110
Drug-target residence time (t = 1/koff, where koff is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However,
little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or
related parameters, koff and activation free energy of dissociation (). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to
develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy
landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method
to simulate the binding event of the anti-Alzheimer’s disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE).
The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values
of binding free energy and activation free energies of association and dissociation deviate from the experimental data only
by less than 1 kcal/mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which
may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery
and development.
Co-reporter:Yanyan Mao, Yun Du, Xiaohui Cang, Jinan Wang, Zhuxi Chen, Huaiyu Yang, and Hualiang Jiang
The Journal of Physical Chemistry B 2013 Volume 117(Issue 3) pp:850-858
Publication Date(Web):December 27, 2012
DOI:10.1021/jp310163z
Ion mixtures are prevalent in both cytosol and the exterior of a plasma membrane with variable compositions and concentrations. Although abundant MD simulations have been performed to study the effects of single ion species on the structures of lipid bilayers, our understanding of the influence of the ion mixture on membranes is still limited; for example, the competition mechanism of different ions in binding with lipids is not clearly addressed yet. Here, microsecond MD simulations were carried out to study the effects of the mixtures of Ca2+, Mg2+, Na+, and K+ ions on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) bilayer. It has been revealed that the binding efficiency of these ions with POPG lipids is in the following order, Ca2+ > Mg2+ > Na+ > K+. The binding free energy of Ca2+ to the lipid bilayer is ∼−4.0 kcal/mol, which is much lower than those of other ions. This result explains why the effects of the ion mixture on membranes are particularly sensitive to the concentration of calcium. The on-rates of different ions do not have a large difference, while the off-rate of Ca2+ is 2–3 orders of magnitude smaller than those of the others. Therefore, the strongest binding affinity of Ca2+ is mainly determined by its smallest off-rate. In addition, our study suggests that the structure of the lipid bilayer is influenced dominantly by the concentration of Ca2+ ions. The simulation results also provide a good explanation for a variety of biological processes relevant to Ca2+ and Mg2+ regulations, such as membrane fusion.
Co-reporter:Xiaohui Cang, Yun Du, Yanyan Mao, Yuanyuan Wang, Huaiyu Yang, and Hualiang Jiang
The Journal of Physical Chemistry B 2013 Volume 117(Issue 4) pp:1085-1094
Publication Date(Web):January 8, 2013
DOI:10.1021/jp3118192
Cholesterol, an abundant membrane component in both lipid rafts and caveolae of cell membrane, plays a crucial role in regulating the function and organization of various G-protein coupled receptors (GPCRs). However, the underlying mechanism for cholesterol-GPCR interaction is still unclear. To this end, we performed a series of microsecond molecular dynamics (MD) simulations on β2-adrenergic receptor (β2AR) in the presence and absence of cholesterol molecules in the POPC bilayer. The unbiased MD simulation on the system with cholesterols reveals that cholesterol molecules can spontaneously diffuse to seven sites on the β2AR surfaces, three in the extracellular leaflet (e1–e3) and four in the intracellular leaflet (i1, i2, i4, and i5). The MD simulation identifies three cholesterol-binding sites (i2, e2, and e3) that are also observed in the crystal structures of several GPCRs. Cholesterol binding to site e1 lock Trp3137.40 into a certain conformation that may facilitate ligand–receptor binding, and cholesterol binding to site i2 provides a structural support for the reported cholesterol-mediate dimeric form of β2AR (PDB code 2RH1). In addition, both competitive and cooperative effects between cholesterols and phospholipids in binding to β2AR were observed in our MD simulations. Together, these results provide new insights into cholesterol–GPCR interactions.
Co-reporter:Yun Du ; Huaiyu Yang ; Yechun Xu ; Xiaohui Cang ; Cheng Luo ; Yanyan Mao ; Yuanyuan Wang ; Guangrong Qin ; Xiaomin Luo
Journal of the American Chemical Society 2012 Volume 134(Issue 15) pp:6720-6731
Publication Date(Web):February 8, 2012
DOI:10.1021/ja211941d
ErbB4, a receptor tyrosine kinase of the ErbB family, plays crucial roles in cell growth and differentiation, especially in the development of the heart and nervous system. Ligand binding to its extracellular region could modulate the activation process. To understand the mechanism of ErbB4 activation induced by ligand binding, we performed one microsecond molecular dynamics (MD) simulations on the ErbB4 extracellular region (ECR) with and without its endogenous ligand neuregulin1β (NRG1β). The conformational transition of the ECR-ErbB4/NRG1β complex from a tethered inactive conformation to an extended active-like form has been observed, while such large and function-related conformational change has not been seen in the simulation on the ECR-ErbB4, suggesting that ligand binding is indeed the active inducing force for the conformational transition and further dimerization. On the basis of MD simulations and principal component analysis, we constructed a rough energy landscape for the conformational transition of ECR-ErbB4/NRG1β complex, suggesting that the conformational change from the inactive state to active-like state involves a stable conformation. The energy barrier for the tether opening was estimated as ∼2.7 kcal/mol, which is very close to the experimental value (1–2 kcal/mol) reported for ErbB1. On the basis of the simulation results, an atomic mechanism for the ligand-induced activation of ErbB4 was postulated. The present MD simulations provide a new insight into the conformational changes underlying the activation of ErbB4.
Co-reporter:Guan Wang ; Zheng Liu ; Tiantian Chen ; Zhen Wang ; Huaiyu Yang ; Mingyue Zheng ; Jing Ren ; Guanghui Tian ; Xiaojun Yang ; Li Li ; Jianfeng Li ; Jin Suo ; Rongxia Zhang ; Xiangrui Jiang ; Nicholas Kenneth Terrett ; Jingshan Shen ; Yechun Xu
Journal of Medicinal Chemistry 2012 Volume 55(Issue 23) pp:10540-10550
Publication Date(Web):November 8, 2012
DOI:10.1021/jm301159y
Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
Co-reporter:Si-sheng Ou-Yang;Jun-yan Lu;Xiang-qian Kong;Zhong-jie Liang;Cheng Luo;Hualiang Jiang
Acta Pharmacologica Sinica 2012 33(9) pp:1131-1140
Publication Date(Web):2012-08-27
DOI:10.1038/aps.2012.109
Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field.
Co-reporter:Fei Wang, Dongxiang Liu, Heyao Wang, Cheng Luo, Mingyue Zheng, Hong Liu, Weiliang Zhu, Xiaomin Luo, Jian Zhang, and Hualiang Jiang
Journal of Chemical Information and Modeling 2011 Volume 51(Issue 11) pp:2821-2828
Publication Date(Web):September 28, 2011
DOI:10.1021/ci200264h
The three-dimensional (3D) structures of most protein targets have not been determined so far, with many of them not even having a known ligand, a truly general method to predict ligand–protein interactions in the absence of three-dimensional information would be of great potential value in drug discovery. Using the support vector machine (SVM) approach, we constructed a model for predicting ligand–protein interaction based only on the primary sequence of proteins and the structural features of small molecules. The model, trained by using 15 000 ligand–protein interactions between 626 proteins and over 10 000 active compounds, was successfully used in discovering nine novel active compounds for four pharmacologically important targets (i.e., GPR40, SIRT1, p38, and GSK-3β). To our knowledge, this is the first example of a successful sequence-based virtual screening campaign, demonstrating that our approach has the potential to discover, with a single model, active ligands for any protein.
Co-reporter:Mingyue Zheng, Bing Xiong, Cheng Luo, Shanshan Li, Xian Liu, Qianchen Shen, Jing Li, Weiliang Zhu, Xiaomin Luo, and Hualiang Jiang
Journal of Chemical Information and Modeling 2011 Volume 51(Issue 11) pp:2994-3004
Publication Date(Web):October 15, 2011
DOI:10.1021/ci2003939
Hydrogen bonding is a key contributor to the molecular recognition between ligands and their host molecules in biological systems. Here we develop a novel orientation-dependent hydrogen bonding potential based on the geometric characteristics of hydrogen bonds observed in 44,585 protein–ligand complexes. We find a close correspondence between the empirical knowledge and the energy landscape inferred from the distribution of HBs. A scoring function based on the resultant hydrogen-bonding potentials discriminates native protein–ligand structures from incorrectly docked decoys with remarkable predictive power.
Co-reporter:Qiancheng Shen, Bing Xiong, Mingyue Zheng, Xiaomin Luo, Cheng Luo, Xian Liu, Yun Du, Jing Li, Weiliang Zhu, Jingkang Shen, and Hualiang Jiang
Journal of Chemical Information and Modeling 2011 Volume 51(Issue 2) pp:386-397
Publication Date(Web):December 30, 2010
DOI:10.1021/ci100343j
Fast and accurate predicting of the binding affinities of large sets of diverse protein−ligand complexes is an important, yet extremely challenging, task in drug discovery. The development of knowledge-based scoring functions exploiting structural information of known protein−ligand complexes represents a valuable contribution to such a computational prediction. In this study, we report a scoring function named IPMF that integrates additional experimental binding affinity information into the extracted potentials, on the assumption that a scoring function with the “enriched” knowledge base may achieve increased accuracy in binding affinity prediction. In our approach, the functions and atom types of PMF04 were inherited to implicitly capture binding effects that are hard to model explicitly, and a novel iteration device was designed to gradually tailor the initial potentials. We evaluated the performance of the resultant IPMF with a diverse set of 219 protein−ligand complexes and compared it with seven scoring functions commonly used in computer-aided drug design, including GLIDE, AutoDock4, VINA, PLP, LUDI, PMF, and PMF04. While the IPMF is only moderately successful in ranking native or near native conformations, it yields the lowest mean error of 1.41 log Ki/Kd units from measured inhibition affinities and the highest Pearson’s correlation coefficient of Rp2 0.40 for the test set. These results corroborate our initial supposition about the role of “enriched” knowledge base. With the rapid growing volume of high-quality structural and interaction data in the public domain, this work marks a positive step toward improving the accuracy of knowledge-based scoring functions in binding affinity prediction.
Co-reporter:Jing Lu;Mingyue Zheng;Yong Wang
Journal of Computer-Aided Molecular Design 2011 Volume 25( Issue 9) pp:
Publication Date(Web):2011 September
DOI:10.1007/s10822-011-9472-7
Skin sensitization is an important toxic endpoint in the risk assessment of chemicals. In this paper, structure–activity relationships analysis was performed on the skin sensitization potential of 357 compounds with local lymph node assay data. Structural fragments were extracted by GASTON (GrAph/Sequence/Tree extractiON) from the training set. Eight fragments with accuracy significantly higher than 0.73 (p < 0.1) were retained to make up an indicator descriptor fragment. The fragment descriptor and eight other physicochemical descriptors closely related to the endpoint were calculated to construct the recursive partitioning tree (RP tree) for classification. The balanced accuracy of the training set, test set I, and test set II in the leave-one-out model were 0.846, 0.800, and 0.809, respectively. The results highlight that fragment-based RP tree is a preferable method for identifying skin sensitizers. Moreover, the selected fragments provide useful structural information for exploring sensitization mechanisms, and RP tree creates a graphic tree to identify the most important properties associated with skin sensitization. They can provide some guidance for designing of drugs with lower sensitization level.
Co-reporter:Chunyi Jiang;Yu Feng;Xiaotong Huang;Yechun Xu
Analytical and Bioanalytical Chemistry 2010 Volume 396( Issue 5) pp:1745-1754
Publication Date(Web):2010 March
DOI:10.1007/s00216-009-3420-6
Aβ1–42 is the proteolytic cleavage product of cleavage of the amyloid precursor protein by β- and γ-secretases. The aggregation of Aβ1–42 plays a causative role in the development of Alzheimer’s disease. To lock Aβ1–42 in a homogenous state, we embedded the Aβ1–42 sequence in an unstructured region of Bcl-xL. Both the N-terminus and the C-terminus of Aβ1–42 were constrained in the disordered region, whereas the conjunction did not introduce any folding to Aβ1–42 but maintained the sequence as a monomer in solution. With Bcl-xL-Aβ42, we developed an enzyme-linked immunosorbent assay to compare the affinity of compounds for monomeric Aβ1–42. Bcl-xL-Aβ42 was coated on a microplate and this was followed by incubation with different concentrations of compounds. Compounds binding to Leu17-Val24 of Aβ1–42 inhibited the interaction between Bcl-xL-Aβ42 and antibody 4G8. The method can not only reproduce the activities of the reported Aβ1–42 inhibitors such as dopamine, tannin, and morin but can also differentiate decoy compounds that do not bind to Aβ1–42. Remarkably, using this method, we discovered a new inhibitor that binds to monomeric Aβ1–42 and inhibits Aβ1–42 fibril formation. As the structure of Bcl-xL-Aβ42 monomer is stable in solution, the assay could be adapted for high-throughput screening with a series of antibodies that bind the different epitopes of Aβ1–42. In addition, the monomeric form of the Aβ1–42 sequence in Bcl-xL-Aβ42 would also facilitate the identification of Aβ1–42 binding partners by coimmunoprecipitation, cocrystallization, surface plasmon resonance technology, or the assay as described here.
Co-reporter:Guangrong Qin, Kunqian Yu, Ting Shi, Cheng Luo, Guohui Li, Weiliang Zhu and Hualiang Jiang
The Journal of Physical Chemistry B 2010 Volume 114(Issue 25) pp:8487-8493
Publication Date(Web):June 3, 2010
DOI:10.1021/jp911588y
Antiflu drugs such as amantadine (AMT) were reported to be insensitive to influenza A virus gradually after their marketing. Mutation experiments indicate that the trans-membrane domain of M2 protein plays an essential role in AMT resistance, especially the S31N mutation. To investigate the details of structure and mechanism, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations have been carried out on both the wild-type protein and its S31N mutant. Our MD simulations reveal AMT can occupy different binding positions in the pore of M2 channel, and the binding modes have also been verified and analyzed by QM/MM calculations. More importantly, we find the formation of a water wire modulated by the binding position of AMT to be essential for the function of M2 protein, and, the block of water wire can inhibit channel function in the WT system. Failure of channel blocking would cause AMT drug resistance in the S31N mutant. These results support one of the conflicting views about M2−drug binding sites: AMT binds to the pore of M2 channel. Our findings help clarify the resistant mechanism of AMT to M2 protein and should facilitate the discovery of new drugs for treating influenza A virus.
Co-reporter:Zhongjie Liang, Ting Shi, Sisheng Ouyang, Honglin Li, Kunqian Yu, Weiliang Zhu, Cheng Luo and Hualiang Jiang
The Journal of Physical Chemistry B 2010 Volume 114(Issue 36) pp:11927-11933
Publication Date(Web):August 20, 2010
DOI:10.1021/jp1054183
Sir2, the histone deacetylase III family, has been subjected to a wide range of studies because of their crucial roles in DNA repair, longevity, transcriptional silencing, genome stability, apoptosis, and fat mobilization. The enzyme binds NAD+ and acetyllysine as substrates and generates lysine, 2′-O-acetyl-ADP-ribose, and nicotinamide as products. However, the mechanism of the first step in Sir2 deacetylation reaction from various studies is controversial. To characterize this catalytic mechanism of acetyllysine deacetylation by Sir2, we employed a combined computational approach to carry out molecular modeling, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) calculations on catalysis by both yeast Hst2 (homologue of SIR two 2) and bacterial Sir2TM (Sir2 homologue from Thermatoga maritima). Our three-dimensional (3D) model of the complex is composed of Sir2 protein, NAD+, and acetyllysine (ALY) substrate. A 15-ns MD simulation of the complex revealed that Gln115 and His135 play a determining role in deacetylation. These two residues can act as bases to facilitate the deprotonation of 2′-OH from N-ribose. The result is in great agreement with previous mutagenesis analysis data. QM/MM calculations were further performed to study the mechanism of the first step in deacetylation in the two systems. The predicted potential energy barriers for yHst2 and Sir2TM are 12.0 and 15.7 kcal/mol, respectively. The characteristics of the potential energy surface indicated this reaction belongs to a SN2-like mechanism. These results provide insights into the Sir2 mechanism of nicotinamide inhibition and have important implications for the discovery of effectors against Sir2 enzymes.
Co-reporter:Huaiyu Yang, Yechun Xu, Zhaobing Gao, Yanyan Mao, Yun Du, and Hualiang Jiang
The Journal of Physical Chemistry B 2010 Volume 114(Issue 50) pp:16978-16988
Publication Date(Web):December 2, 2010
DOI:10.1021/jp1091569
Ion−membrane interactions are essential to the regulation of cell functions. While numerous molecular dynamics (MD) simulations have been carried out to study the effects of ions on neutral lipid bilayers, few have been conducted on anionic lipid bilayers. Moreover, there is a lack of long-time simulations. Here, submicrosecond MD simulations were performed to investigate the effects of pure cations (K+, Na+, and Ca2+, respectively) on the anionic palmitoyloleoylphosphatidylglycerol (POPG) bilayer first. The results reveal how K+, Na+, and Ca2+ ions influence the structure of anionic lipid bilayers. In general, cations tighten the anionic lipid bilayer and increase the ordering of the lipids. Subsequently, two MD simulations were carried out to elucidate the effects of extra cations added to the bilayers in addition to counterions. It is found that the extra Ca2+ ions result in stronger effects on the structures of the lipid bilayer, whereas extra Na+ ions do not. Finally, simulations of ion mixture effects on the structure of the POPG bilayer were conducted, and it is observed that Ca2+, over K+ and Na+, plays a dominant role in affecting the bilayer structures. These results may cast new insights on the distinct functions of Ca2+ in the biological systems. In addition, our simulations indicate that long-time simulations are necessary to address the effects of ions on lipid bilayer structures.
Co-reporter:Lingyan He ; Liang Zhang ; Xiaofeng Liu ; Xianghua Li ; Mingyue Zheng ; Honglin Li ; Kunqian Yu ; Kaixian Chen ; Xu Shen ; Hualiang Jiang ;Hong Liu
Journal of Medicinal Chemistry 2009 Volume 52(Issue 8) pp:2465-2481
Publication Date(Web):March 23, 2009
DOI:10.1021/jm8015602
The discovery of HpFabZ inhibitors is now of special interest in the treatment of various gastric diseases. In this work, three series of derivatives (compounds 3, 4, and 5) were designed, synthesized, and their biological activities were investigated as potential HpFabZ inhibitors in a two phased manner. First, we designed and synthesized two series of derivatives (3a−r and 4a−u) and evaluated the enzyme-based assay against HpFabZ. Five compounds (3i−k, 3m, and 3q) showed potential inhibitory activity, with IC50 values less than 2 μM. Second, a focused combinatorial library containing 280 molecules was designed employing the LD1.0 program. Twelve compounds (5a−l) were selected and synthesized. The activity of the most potent compound 5h (IC50 = 0.86 μM) was 46 times higher than that of the hit 1. The high hit rate and the potency of the new HpFabZ inhibitors demonstrated the efficiency of the strategy for the focused library design and virtual screening.
Co-reporter:Honglin Li ; Jin Huang ; Lili Chen ; Xiaofeng Liu ; Tong Chen ; Jin Zhu ; Weiqiang Lu ; Xu Shen ; Jian Li ; Rolf Hilgenfeld
Journal of Medicinal Chemistry 2009 Volume 52(Issue 15) pp:4936-4940
Publication Date(Web):July 8, 2009
DOI:10.1021/jm801622x
The SPECS database was screened against falcipain-2 with two different docking methods to identify structurally diverse nonpeptidic inhibitors. Twenty-eight nonpeptidic molecules among 81 compounds tested were identified as potential inhibitors of falcipain-2. One of the inhibitors exhibited in vitro activity with an IC50 value of 2.4 μM. Furthermore, the similarity analysis has demonstrated that it is feasible to find novel diverse falcipain-2 inhibitors with similar steric shape through virtual screening of large-scale chemical libraries.
Co-reporter:Ling Kang;Honglin Li;Xiaoyu Zhao
Journal of Mathematical Chemistry 2009 Volume 46( Issue 1) pp:
Publication Date(Web):2009 June
DOI:10.1007/s10910-008-9454-8
In this paper, we present a multi-scale optimization model and an entropy-based genetic algorithm for molecular docking. In this model, we introduce to the refined docking design a concept of residue groups based on induced-fit and adopt a combination of conformations in different scales. A new iteration scheme, in conjunction with multi-population evolution strategy, entropy-based searching technique with narrowing down space and the quasi-exact penalty function, is developed to address the optimization problem for molecular docking. A new docking program that accounts for protein flexibility has also been developed. The docking results indicate that the method can be efficiently employed in structure-based drug design.
Co-reporter:Xiaoyu Zhao, Xiaofeng Liu, Yuanyuan Wang, Zhi Chen, Ling Kang, Hailei Zhang, Xiaomin Luo, Weiliang Zhu, Kaixian Chen, Honglin Li, Xicheng Wang and Hualiang Jiang
Journal of Chemical Information and Modeling 2008 Volume 48(Issue 7) pp:1438-1447
Publication Date(Web):June 14, 2008
DOI:10.1021/ci7004719
An improved potential mean force (PMF) scoring function, named KScore, has been developed by using 23 redefined ligand atom types and 17 protein atom types, as well as 28 newly introduced atom types for nucleic acids (DNA and RNA). Metal ions and water molecules embedded in the binding sites of receptors are considered explicitly by two newly defined atom types. The individual potential terms were devised on the basis of the high-resolution crystal and NMR structures of 2422 protein−ligand complexes, 300 DNA−ligand complexes, and 97 RNA−ligand complexes. The optimized atom pairwise distances and minima of the potentials overcome some of the disadvantages and ambiguities of current PMF potentials; thus, they more reasonably explain the atomic interaction between receptors and ligands. KScore was validated against five test sets of protein−ligand complexes and two sets of nucleic-acid−ligand complexes. The results showed acceptable correlations between KScore scores and experimentally determined binding affinities (log Kiʼs or binding free energies). In particular, KScore can be used to rank the binding of ligands with metalloproteins; the linear correlation coefficient (R) for the test set is 0.65. In addition to reasonably ranking protein−ligand interactions, KScore also yielded good results for scoring DNA/RNA−-ligand interactions; the linear correlation coefficients for DNA−ligand and RNA−ligand complexes are 0.68 and 0.81, respectively. Moreover, KScore can appropriately reproduce the experimental structures of ligand−receptor complexes. Thus, KScore is an appropriate scoring function for universally ranking the interactions of ligands with protein, DNA, and RNA.
Co-reporter:JiaGao Cheng;WeiLiang Zhu;YanLi Wang;XiuHua Yan
Science China Chemistry 2008 Volume 51( Issue 8) pp:
Publication Date(Web):2008 August
DOI:10.1007/s11426-008-0087-3
The M2 protein from influenza A virus is a tetrameric ion channel. It was reported that the permeation of the ion channel is correlated with the hydrogen bond network among His37 residues and the cation-π interactions between His37 and Trp41. In the present study, the hydrogen bonding network of 4-methyl-imidazoles was built to mimic the hydrogen bonds between His37 residues, and the cation-π interactions between 4-methyl-imidazolium and indole systems were selected to represent the interactions between His37 and Trp41. Then, quantum chemistry calculations at the MP2/6-311G** level were carried out to explore the properties of the hydrogen bonds and the cation-π interactions. The calculation results indicate that the binding strength of the N-H…N hydrogen bond between imidazole rings is up to −6.22 kcal·mol−1, and the binding strength of the strongest cation-π interaction is up to −18.8 kcal·mol−1 (T-shaped interaction) or −12.3 kcal·mol−1 (parallel stacking interaction). Thus, the calculated binding energies indicate that it is possible to control the permeation of the M2 ion channel through the hydrogen bond network and the cation-π interactions by altering the pH values.
Co-reporter:Mingfang Zheng, Chenghui Xu, Jianwei Ma, Yan Sun, Feifei Du, Hong Liu, Liping Lin, Chuan Li, Jian Ding, Kaixian Chen, Hualiang Jiang
Bioorganic & Medicinal Chemistry 2007 Volume 15(Issue 4) pp:1815-1827
Publication Date(Web):15 February 2007
DOI:10.1016/j.bmc.2006.11.028
A series of triaminotriazine derivatives (compounds 5a–f, 6a–x, and 7a–g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 μM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure–activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 μM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.By structural modification of the screening hit (4,6-bis(N-morpholino)-[1,3,5]triazin-2-yl)-phenylamine (5a), four compounds exhibited higher inhibition activities against HCT-116 with IC50 values below 5 μM. Compounds 6l and 6o were most prominent against HCT-116, with IC50s of 0.76 and 0.92 μM, respectively.
Co-reporter:Mingfang Zheng, Mingyue Zheng, Deju Ye, Yangmei Deng, Shuifeng Qiu, Xiaomin Luo, Kaixian Chen, Hong Liu, Hualiang Jiang
Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 9) pp:2414-2420
Publication Date(Web):1 May 2007
DOI:10.1016/j.bmcl.2007.02.038
A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC50 = 74 μM). Selected compounds for concentration–response studies showed prominent inhibitory activities with IC50 values ranging from 0.74 μM to 3.17 μM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC50 values less than 1 μM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.Four compounds (1m, 1s, 4a, and 6a) exhibited the potent inhibitory activity against 5-LOX in rat peritoneal leukocytes, with IC50 values ranging from 0.74 μM to 0.95 μM, which is very close to the reference drug (Zileuton, IC50 = 0.83 μM).
Co-reporter:Aijun Lu, Jian Zhang, Xiaojin Yin, Xiaomin Luo, Hualiang Jiang
Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 1) pp:243-249
Publication Date(Web):1 January 2007
DOI:10.1016/j.bmcl.2006.09.055
A three-dimensional pharmacophore model was developed based on 25 currently available inhibitors, which were carefully selected with great diversity in both molecular structure and bioactivity as required by HypoGen program in the Catalyst software, for discovering new farnesyltransferase (FTase) inhibitors. The best hypothesis (Hypo1), consisting of four features, namely, two hydrogen-bond acceptors, one hydrophobic point, and one ring aromatic feature, has a correlation coefficient of 0.949, a root-mean-square deviation of 1.321, and a cost difference of 163.15, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of 227 known FTase inhibitors in our test set with a correlation coefficient of 0.776 with a cross-validation of 98% confidence level. Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity.The best pharmacophore model produced in Catalyst 4.10 by 25 farnesyltransferase inhibitors in training set. It consists of four features, two hydrogen-bond acceptors (HA), one hydrophobic point (HY), and one ring aromatic feature (RA).
Co-reporter:Jiagao Cheng;Zhen Gong;Weiliang Zhu;Yun Tang;Weihua Li;Zhong Li
Journal of Physical Organic Chemistry 2007 Volume 20(Issue 7) pp:448-453
Publication Date(Web):17 APR 2007
DOI:10.1002/poc.1175
Quantum chemistry study was performed on interaction between tetramethylammonium (TMA) and aromatic cages by means of the MP2 method to show how TMA sits in an aromatic cage that is composed of benzenes. The MP2 calculations on TMA–(benzene)n complexes demonstrate that the more the benzene molecules in the aromatic cage, the stronger the binding strength between the cage and TMA. In details, the structure of TMA–(benzene)n (n = 1–4) complexes can be easily constructed by superimposing n TMA-benzene complexes via TMA, and the binding energies of the TMA–(benzene)n complexes are the sum of the n corresponding TMA-benzene systems. For instance, the distances between the N of TMA and the plane of the benzene ring are 4.238, 4.252, 4.264 ,and 4.276 Å, respectively, for TMA–(benzene)n (n = 1–4) complexes, and the BSSE corrected binding energies at MP2/6-311++G** level are −8.8, −17.3, −25.8 and −34.3 kcal/mol, respectively, for TMA– (benzene)n (n = 1–4) complexes. Thus, this study provides us useful information on how a cation interacts with an aromatic cage in terms of complex geometry and binding strength. Copyright © 2007 John Wiley & Sons, Ltd.
Co-reporter:Tao Sun Dr.;Qi Wang Dr.;Zhiguo Yu Dr.;Yu Zhang Dr.;Yuewei Guo ;Kaixian Chen ;Xu Shen
ChemBioChem 2007 Volume 8(Issue 2) pp:
Publication Date(Web):20 DEC 2006
DOI:10.1002/cbic.200600349
Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling, and PTP1B inhibitors have been seen as promising therapeutic agents against obesity and type 2 diabetes. Here we report that the marine natural product hyrtiosal, from the marine sponge Hyrtios erectus, has been discovered to act as a PTP1B inhibitor and to show extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFβ/Smad2 signaling. This inhibitor wad able to inhibit PTP1B activity in dose-dependent fashion, with an IC50 value of 42 μM in a noncompetitive inhibition mode. Further study with an IN Cell Analyzer 1000 cellular fluorescence imaging instrument showed that hyrtiosal displayed potent activity in abolishing the retardation of AKT membrane translocation caused by PTP1B overexpression in CHO cells. Moreover, it was found that this newly identified PTP1B inhibitor could dramatically enhance the membrane translocation of the key glucose transporter Glut4 in PTP1B-overexpressed CHO cells. Additionally, in view of our recent finding that PTP1B was able to modulate insulin-mediated inhibition of Smad2 activation, hyrtiosal was also tested for its capabilities in the regulation of Smad2 activity through the PI3K/AKT pathway. The results showed that hyrtiosal could effectively facilitate insulin inhibition of Smad2 activation. Our current study is expected to supply new clues for the discovery of PTP1B inhibitors from marine natural products, while the newly identified PTP1B inhibitor hyrtiosal might serve as a potential lead compound for further research.
Co-reporter:Jian Zhang;Juwen Shen;Weiliang Zhu;Kunqian Yu;Xiaomin Luo;Kaixian Chen;Yixue Li
PNAS 2007 Volume 104 (Issue 11 ) pp:4337-4341
Publication Date(Web):2007-03-13
DOI:10.1073/pnas.0607879104
Protein–protein interactions (PPIs) are central to most biological processes. Although efforts have been devoted to the development
of methodology for predicting PPIs and protein interaction networks, the application of most existing methods is limited because
they need information about protein homology or the interaction marks of the protein partners. In the present work, we propose
a method for PPI prediction using only the information of protein sequences. This method was developed based on a learning
algorithm-support vector machine combined with a kernel function and a conjoint triad feature for describing amino acids.
More than 16,000 diverse PPI pairs were used to construct the universal model. The prediction ability of our approach is better
than that of other sequence-based PPI prediction methods because it is able to predict PPI networks. Different types of PPI
networks have been effectively mapped with our method, suggesting that, even with only sequence information, this method could
be applied to the exploration of networks for any newly discovered protein with unknown biological relativity. In addition,
such supplementary experimental information can enhance the prediction ability of the method.
Co-reporter:Jian Li, Jing Chen, Chunshan Gui, Li Zhang, Yu Qin, Qiang Xu, Jian Zhang, Hong Liu, Xu Shen, Hualiang Jiang
Bioorganic & Medicinal Chemistry 2006 Volume 14(Issue 7) pp:2209-2224
Publication Date(Web):1 April 2006
DOI:10.1016/j.bmc.2005.11.006
Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis–trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1–15). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds (1–6, 15, 16a–q, 17a–d, and 18a–l), and four of which (compounds 16b, 16h, 16k, and 18g) showed high CypA PPIase inhibition activities with IC50s of 2.5–6.2 μM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.By using structure-based virtual screening approach in conjunction with chemical synthesis and bioassay, four potent CypA inhibitors have been discovered. Compound 16h is active with very close potency to CsA in inhibiting the proliferation of spleen cells, demonstrating that this compound may be a good lead for discovering new immunosuppressive agents.
Co-reporter:Jian Li, Mingyue Zheng, Wei Tang, Pei-Lan He, Weiliang Zhu, Tianxian Li, Jian-Ping Zuo, Hong Liu, Hualiang Jiang
Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 19) pp:5009-5013
Publication Date(Web):1 October 2006
DOI:10.1016/j.bmcl.2006.07.047
Sixteen novel 4-triazole-modified zanamivir (1) analogues were synthesized using the click reactions, and their inhibitory activities against avian influenza virus (AIV, H5N1) were determined. Compound 3b exerts promising inhibitory activity with EC50 of 6.4 μM, which is very close to that of zanamivir (EC50 = 2.8 μM). Molecular modeling provided the information about the binding model between inhibitors and neuraminidase, which are in good agreement with inhibitory activities.Compound 3b, 4-triazole-modified zanamivir analogue, shows anti-AIV (H5N1) activity with EC50 of 6.4 μM, which is very close to that of zanamivir (EC50 = 2.8 μM).
Co-reporter:Jian Zhang, KunQian Yu, Weiliang Zhu, Hualiang Jiang
Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 11) pp:3009-3014
Publication Date(Web):1 June 2006
DOI:10.1016/j.bmcl.2006.02.054
A three-dimensional pharmacophore model was developed based on 22 currently available inhibitors, which were carefully selected with great diversity in both molecular structure and bioactivity, for discovering new potent neuraminidase (NA) inhibitors to fight against avian influenza virus. The best hypothesis (Hypo1), consisting of five features, namely, one positive ionizable group, one negative ionizable group, one hydrophobic point, and two hydrogen-bond donors, has a correlation coefficient of 0.902, a root mean square deviation of 1.392, and a cost difference of 72.88, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of 88 known NA inhibitors in our test set with a correlation coefficient of 0.818 with a cross-validation of 98% confidence level. Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity.A quantitative pharmacophore hypothesis for AIV neuraminidase inhibitors was built based on 22 compounds with great molecular diversity and bioactivity, and validated using 88 compounds to be highly predictive.
Co-reporter:Weiliang Zhu, Gang Chen, Lihong Hu, Xiaomin Luo, Chunshan Gui, Cheng Luo, Chum Mok Puah, Kaixian Chen, Hualiang Jiang
Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 2) pp:313-322
Publication Date(Web):17 January 2005
DOI:10.1016/j.bmc.2004.10.027
Ginkgolides, isolated from ginkgo balba leaves, were found to be powerful as natural antagonists of human platelet activating factor (PAF) in treatment of some diseases such as acute inflammation, tissue rejection, asthma, and ischemic injury. Ginkgolides have a cage skeleton consisting of six five-membered rings, therefore, are very tough to be synthesized. For finding new powerful substitutes of the natural ginkgolides for treating those diseases, three methods, viz. CoMFA, CoMSIA, and HQSAR, were used to investigate the relationship between 117 ginkgolide analogues with great structural diversity and their bioactivities against PAF receptor. The high q2 released from the different QSAR methods, ranging from 0.583 to 0.684, suggests that three rational and predictive QSAR models were successfully built. These models also show clearly how steric, electrostatic, hydrophobicity, and individual atom affect molecular bioactivity as antagonists of PAF. These results could also be used to account for the unusually higher bioactivity of ginkgolide B than other ginkgolides. The possible binding mechanism between ginkgolides and human PAF receptor was also deduced based on the QSAR models. Therefore, this study should be very helpful in discovering new drugs as PAF antagonists in fighting against various diseases related to PAF and PAF receptor.QSAR study was carried out on 117 ginkgolide analogues using the methods of CoMFA, CoMSIA, and HQSAR, for finding new potent substitutes of the natural ginkgolides for treating PAF related diseases. The possible binding mechanism between ginkgolides and human PAF receptor was also deduced based on the QSAR results.
Co-reporter:Jianhua Shen;Yechun Xu;Weiliang Zhu;Kaixian Chen;Xiaomin Luo;Jianpeng Ma
PNAS 2005 Volume 102 (Issue 15 ) pp:5403-5407
Publication Date(Web):2005-04-12
DOI:10.1073/pnas.0501218102
The amyloid β-peptides (Aβs), containing 39–43 residues, are the key protein components of amyloid deposits in Alzheimer's
disease. To structurally characterize the dynamic behavior of Aβ40, 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type
peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an α-helix to β-sheet
conformational transition for Aβ40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with β-sheet components
were observed as intermediates in the unfolding pathway of Aβ40. Four glycines (G25, G29, G33, and G37) are important for Aβ40 to form β-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the β-sheet formation and increased
the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of
Aβ40 is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic
feature revealed by our MD simulations rationalized several experimental observations for Aβ40 aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of
amyloid formation and designing the compounds for inhibiting the aggregation of Aβ and amyloid fibril formation.
Co-reporter:Gang Chen, Xiaomin Luo, Weiliang Zhu, Cheng Luo, Hong Liu, Chum Mok Puah, Kaixian Chen, Hualiang Jiang
Bioorganic & Medicinal Chemistry 2004 Volume 12(Issue 9) pp:2409-2417
Publication Date(Web):1 May 2004
DOI:10.1016/j.bmc.2004.02.001
Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are attractive targets for anti-tumor drug design. Although thousands of their ligands have been studied as potential inhibitors against PTKs, there is no QSAR study that covers different kinds of inhibitors with observable structural diversity. However, by using this approach, we could mine far more useful information. Hence in order to better understand the binding model and the relationship between the physicochemical properties and the inhibitory activities of different kind of various inhibitors, molecular docking and 3D-QSAR, viz. CoMFA and CoMSIA, were combined to study 124 reported inhibitors with different scaffolds. Based on the docked binding conformations, highly reliable and predictive 3D-QSAR models were derived, which reveal how steric, electrostatic, and hydrophobic interactions contribute to inhibitors' bioactivities. This result also demonstrates that it is possible to include different kinds of inhibitors with observable structural diversity into one 3D-QSAR study. Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides new hints for de novo design of new EGFR inhibitors with observable structural diversity.One hundred and twenty four EGFR PTK's inhibitors with different scaffolds were used in CoMFA and CoMSIA studies. Highly reliable and predictive 3D-QSAR models were derived, which reveal how steric, electrostatic, and hydrophobic interactions contribute to inhibitors' bioactivities.
Co-reporter:Honglin Li, Chunlian Li, Chunshan Gui, Xiaomin Luo, Kaixian Chen, Jianhua Shen, Xicheng Wang, Hualiang Jiang
Bioorganic & Medicinal Chemistry Letters 2004 Volume 14(Issue 18) pp:4671-4676
Publication Date(Web):20 September 2004
DOI:10.1016/j.bmcl.2004.06.091
Based on an improved multi-population genetic algorithm, a new fast flexible docking program, GAsDock, was developed. The docking accuracy, screening efficiency, and docking speed of GAsDock were evaluated by the docking results of thymidine kinase (TK) and HIV-1 reverse transcriptase (RT) enzyme with 10 available inhibitors of each protein and 990 randomly selected ligands. Nine of the ten known inhibitors of TK were accurately docked into the protein active site, the root-mean-square deviation (RMSD) values between the docking and X-ray crystal structures are less than 1.7 Å; binding poses (conformation and orientation) of 9 of the 10 known inhibitors of RT were reproduced by GAsDock with RMSD values less than 2.0 Å. The docking time is approximately in proportion to the number of rotatable bonds of ligands; GAsDock can finish a docking simulation within 60 s for a ligand with no more than 20 rotatable bonds. Results indicate that GAsDock is an accurate and remarkably faster docking program in comparison with other docking programs, which is applausive in the application of virtual screening.A new rapid accurate flexible docking program, GAsDock, was developed based on an improved multi-population genetic algorithm. Its rapid docking speed and excellent accuracy are efficient enough for virtual screening toward large-scale chemical databases.
Co-reporter:Haibin Luo, Fei Ye, Tao Sun, Liduo Yue, Shuying Peng, Jing Chen, Guowei Li, Yi Du, Youhua Xie, Yiming Yang, Jianhua Shen, Yuan Wang, Xu Shen, Hualiang Jiang
Biophysical Chemistry 2004 Volume 112(Issue 1) pp:15-25
Publication Date(Web):1 December 2004
DOI:10.1016/j.bpc.2004.06.008
The major biochemical and thermodynamic features of nucelocapsid protein of SARS coronavirus (SARS_NP) were characterized by use of non-denatured gel electrophoresis, size-exclusion chromatographic and surface plasmon resonance (SPR) techniques. The results showed that SARS_NP existed in vitro as oligomer, more probably dimer, as the basic functional unit. This protein shows its maximum conformational stability near pH 9.0, and it seems that its oligomer dissociation and protein unfolding occur simultaneously. Thermal-induced unfolding for SARS_NP was totally irreversible. Both the thermal and chemical denaturant-induced denaturation analyses showed that oligomeric SARS_NP unfolds and refolds through a two-state model, and the electrostatic interactions among the charge groups of SARS_NP made a significant contribution to its conformational stability.
Co-reporter:Mingyue Zheng, Xian Liu, Yuan Xu, Honglin Li, Cheng Luo, Hualiang Jiang
Trends in Pharmacological Sciences (October 2013) Volume 34(Issue 10) pp:549-559
Publication Date(Web):1 October 2013
DOI:10.1016/j.tips.2013.08.004
•The leading computational techniques for drug design and discovery are reviewed.•Successful applications of computational techniques are provided.•A novel drug–target binding kinetics calculation approach is introduced.In the past decades, China's computational drug design and discovery research has experienced fast development through various novel methodologies. Application of these methods spans a wide range, from drug target identification to hit discovery and lead optimization. In this review, we firstly provide an overview of China's status in this field and briefly analyze the possible reasons for this rapid advancement. The methodology development is then outlined. For each selected method, a short background precedes an assessment of the method with respect to the needs of drug discovery, and, in particular, work from China is highlighted. Furthermore, several successful applications of these methods are illustrated. Finally, we conclude with a discussion of current major challenges and future directions of the field.
Co-reporter:Weizhi Liu, Li Du, Liang Zhang, Jing Chen, Xu Shen, Hualiang Jiang
Protein Expression and Purification (March 2007) Volume 52(Issue 1) pp:74-81
Publication Date(Web):1 March 2007
DOI:10.1016/j.pep.2006.09.003
Acyl carrier protein (ACP) is an essential component in the type II fatty acid biosynthesis (FAS II) process and is responsible for the acyl group transfer within a series of related enzymes. In this work, the ACP from Helicobacter pylori strain SS1 was cloned and the gene sequence of Hpacp was deposited in the GenBank database (Accession No.: AY904356). Two forms of HpACP (apo, holo) were successfully purified and characterized. The thermal stability of these two forms was quantitatively investigated by CD spectral analyses. The results revealed that the holo-HpACP was more stable than apo-HpACP according to the transition midpoint temperature(Tm). Moreover, the interaction of HpACP with the related enzyme (β-hydroxyacyl-ACP dehydratase, HpFabZ) was determined by GST-pull down assay and surface plasmon resonance (SPR) technique in vitro, the results showed that HpACP displays a strong binding affinity to HpFabZ (KD = 1.2 × 10−8 M). This current work is hoped to supply useful information for better understanding the ACP features of Helicobacter pylori SS1 strain.
Co-reporter:Ye Yu, Zhi Chen, Wei-Guang Li, Hui Cao, ... Tian-Le Xu
Neuron (6 October 2010) Volume 68(Issue 1) pp:61-72
Publication Date(Web):6 October 2010
DOI:10.1016/j.neuron.2010.09.001
Acid-sensing ion channels (ASICs) have long been considered as extracellular proton (H+)-gated cation channels, and peripheral ASIC3 channels seem to be a natural sensor of acidic pain. Here, we report the identification of a nonproton sensor on ASIC3. We show first that 2-guanidine-4-methylquinazoline (GMQ) causes persistent ASIC3 channel activation at the normal pH. Using GMQ as a probe and combining mutagenesis and covalent modification analysis, we then uncovered a ligand sensor lined by residues around E423 and E79 of the extracellular “palm” domain of the ASIC3 channel that is crucial for activation by nonproton activators. Furthermore, we show that GMQ activates sensory neurons and causes pain-related behaviors in an ASIC3-dependent manner, indicating the functional significance of ASIC activation by nonproton ligands. Thus, natural ligands beyond protons may activate ASICs under physiological and pathological conditions through the nonproton ligand sensor, serving for channel activation independent of abrupt and marked acidosis.Highlights► A nonproton ligand sensor exists in the acid-sensing ion channels ► Nonproton ligand causes persistent activations of acid-sensing ion channels ► A single covalent modification of E79 locks ASIC3 channels in the open state ► Natural ligands beyond protons may activate acid-sensing ion channels
Co-reporter:Tiancen Hu, Yu Zhang, Lianwei Li, Kuifeng Wang, Shuai Chen, Jing Chen, Jianping Ding, Hualiang Jiang, Xu Shen
Virology (5 June 2009) Volume 388(Issue 2) pp:324-334
Publication Date(Web):5 June 2009
DOI:10.1016/j.virol.2009.03.034
The 3C-like protease of SARS coronavirus (SARS-CoV 3CLpro) is vital for SARS-CoV replication and is a promising drug target. It has been extensively proved that only the dimeric enzyme is active. Here we discovered that two adjacent mutations (Ser139_Ala and Phe140_Ala) on the dimer interface resulted in completely different crystal structures of the enzyme, demonstrating the distinct roles of these two residues in maintaining the active conformation of SARS-CoV 3CLpro. S139A is a monomer that is structurally similar to the two reported monomers G11A and R298A. However, this mutant still retains a small fraction of dimer in solution, which might account for its remaining activity. F140A is a dimer with the most collapsed active pocket discovered so far, well-reflecting the stabilizing role of this residue. Moreover, a plausible dimerization mechanism was also deduced from structural analysis. Our work is expected to provide insight on the dimerization–function relationship of SARS-CoV 3CLpro.
Co-reporter:Huaiyu Yang, Zhaobing Gao, Ping Li, Kunqian Yu, Ye Yu, Tian-Le Xu, Min Li, Hualiang Jiang
Biophysical Journal (18 April 2012) Volume 102(Issue 8) pp:
Publication Date(Web):18 April 2012
DOI:10.1016/j.bpj.2012.03.032
Voltage sensing confers conversion of a change in membrane potential to signaling activities underlying the physiological processes. For an ion channel, voltage sensitivity is usually experimentally measured by fitting electrophysiological data to Boltzmann distributions. In our study, a two-state model of the ion channel and equilibrium statistical mechanics principle were used to test the hypothesis of empirically calculating the overall voltage sensitivity of an ion channel on the basis of its closed and open conformations, and determine the contribution of individual residues to the voltage sensing. We examined the theoretical paradigm by performing experimental measurements with Kv1.2 channel and a series of mutants. The correlation between the calculated values and the experimental values is at respective level, R2 = 0.73. Our report therefore provides in silico prediction of key conformations and has identified additional residues critical for voltage sensing.
Co-reporter:Wei Fu, Jianhua Shen, Xiaomin Luo, Weiliang Zhu, Jiagao Cheng, Kunqian Yu, James M. Briggs, Guozhang Jin, Kaixian Chen, Hualiang Jiang
Biophysical Journal (1 September 2007) Volume 93(Issue 5) pp:
Publication Date(Web):1 September 2007
DOI:10.1529/biophysj.106.088500
(−)–Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational “open-closed” process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model.
Co-reporter:Huaiyu Yang, Yechun Xu, Weiliang Zhu, Kaixian Chen, Hualiang Jiang
Biophysical Journal (1 February 2007) Volume 92(Issue 3) pp:
Publication Date(Web):1 February 2007
DOI:10.1529/biophysj.106.090191
The mechanism by which the ammonium transporter, AmtB, conducts NH4+/NH3 into the cytoplasm was investigated using conventional molecular dynamics (MD) simulations. These simulations revealed that the neutral molecule, NH3, passes automatically through the channel upon its arrival at the Am2 site and that the function of the channel as a one-way valve for passage of NH3 is not determined by the cytoplasmic exit gate but, rather, by the periplasmic entrance gate of the channel. The NH3, produced by deprotonation of NH4+ at the entrance gate, is spontaneously conveyed to the central region of the channel via a hydrogenbond network comprising His-168, His-318, Tyr-32, and the NH3 molecule. Finally, the NH3 molecule exits the channel through the exit gate formed by Phe-31, Ile-266, Val-314, and His-318. In addition, Ser-263 is shown to play a critical role in the final stages, acting as a pivoting arm to shunt the NH3 molecule from the cytoplasmic exit gate of the channel out into the cytoplasm. This finding is further supported by another simulation which shows that NH3 fails to be translocated through the channel formed by the Ser-263–Ala mutation. Thus, this study casts new insights on the mechanism of AmtB-mediated passage of NH3 across cellular membranes.
![[1(2H),2'-Bipyridin]-2-one, 5-bromo-](http://img.cochemist.com/ccimg/109900/109822-11-9.png)
![[1(2H),2'-Bipyridin]-2-one, 5-bromo-](http://img.cochemist.com/ccimg/109900/109822-11-9_b.png)
![N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(3-methoxyphenyl)acetamide](http://img.cochemist.com/ccimg/67300/67237-63-2.png)
![N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(3-methoxyphenyl)acetamide](http://img.cochemist.com/ccimg/67300/67237-63-2_b.png)
![[1(2H),2'-BIPYRIDIN]-2-ONE, 5-METHYL-](http://img.cochemist.com/ccimg/53500/53427-88-6.png)
![[1(2H),2'-BIPYRIDIN]-2-ONE, 5-METHYL-](http://img.cochemist.com/ccimg/53500/53427-88-6_b.png)
