Recent developments in studies of directed transport processes in interacting particle systems are retrospected. Due to the interactions among elements, the directed transport process exhibits complicated and novel co...Recent developments in studies of directed transport processes in interacting particle systems are retrospected. Due to the interactions among elements, the directed transport process exhibits complicated and novel cooperative dynamics. We considered various possibilities in achieving ratchet motion by breaking different symmetries of many-body systems. It is shown that the directional transport can even be induced by breaking the coupling symmetry and the spatiotemporal symmetries.展开更多
In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and doc...In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies have been performed on 45 pyrido[2,3-d] pyrimidine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model （q2=0.707, R2=0.964） and CoMSIA model （q2=0.645, R2=0.972）. The external validation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen- 2 values of 0.792 and 0.826, the leave-one-out r2m（LOO） values of 0.781 and tim parameter rm2 0.809, r2（ all） values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows： simultaneously introducing high electropositive groups to the sub- stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors.展开更多
Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple...Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：展开更多
目的趋化因子C-C-基元受体5(CCR5受体)是1型艾滋病病毒(HIV-1)入侵靶细胞的关键辅助受体之一,利用计算机辅助药物设计的方法进行虚拟筛选,并进行体外活性测定,以期获得新的CCR5受体抑制剂的先导化合物。方法利用Discovery Studio 2.0软...目的趋化因子C-C-基元受体5(CCR5受体)是1型艾滋病病毒(HIV-1)入侵靶细胞的关键辅助受体之一,利用计算机辅助药物设计的方法进行虚拟筛选,并进行体外活性测定,以期获得新的CCR5受体抑制剂的先导化合物。方法利用Discovery Studio 2.0软件构建HypoGen药效团模型;利用Sybyl-X 2.0软件构建Surflexdock分子对接模型;采用多级筛选的策略,运用"类药五原则"、药效团模型和分子对接模型对ZINC数据库进行逐级筛选;通过检测TZM-bl细胞中荧光素酶报告基因的表达情况来判断化合物的抗HIV-1活性,并通过MTT实验考查化合物的细胞毒性。结果成功构建了药效团和分子对接模型,并对ZINC数据库进行了多级虚拟筛选,得到6个待测化合物(B01-06);活性检测结果证实,B04的IC50为(29.52±3.73)μmol/L,CC50为(181.4±14.22)μmol/L;B06的IC50为(42.13±5.06)μmol/L,CC50为(354.9±28.82)μmol/L。结论化合物B04和B06具有一定的抗HIV-1活性,可作为潜在的先导化合物进行进一步的结构改造。展开更多
Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of...Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis （Hypo2） including one hydrogen-bond donor （D）, one hydrogen-bond acceptor （A）, and two hydrophobic （H） features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.展开更多
Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure...Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.展开更多
In this paper, we consider a system of （2＋2）-dimensional nonlinear models by using CK direct method and Hereman-Nuseir method generated by the Janlent-Miodek Hierarchy. We construct some new multiple kink and singu...In this paper, we consider a system of （2＋2）-dimensional nonlinear models by using CK direct method and Hereman-Nuseir method generated by the Janlent-Miodek Hierarchy. We construct some new multiple kink and singular kink solutions of （2＋1）-Dimensional Nonlinear Models with the aid of symbolic computation.展开更多
文摘Recent developments in studies of directed transport processes in interacting particle systems are retrospected. Due to the interactions among elements, the directed transport process exhibits complicated and novel cooperative dynamics. We considered various possibilities in achieving ratchet motion by breaking different symmetries of many-body systems. It is shown that the directional transport can even be induced by breaking the coupling symmetry and the spatiotemporal symmetries.
文摘In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies have been performed on 45 pyrido[2,3-d] pyrimidine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model （q2=0.707, R2=0.964） and CoMSIA model （q2=0.645, R2=0.972）. The external validation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen- 2 values of 0.792 and 0.826, the leave-one-out r2m（LOO） values of 0.781 and tim parameter rm2 0.809, r2（ all） values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows： simultaneously introducing high electropositive groups to the sub- stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors.
基金Project(20876180)supported by the National Natural Science Foundation of China
文摘Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：
文摘目的趋化因子C-C-基元受体5(CCR5受体)是1型艾滋病病毒(HIV-1)入侵靶细胞的关键辅助受体之一,利用计算机辅助药物设计的方法进行虚拟筛选,并进行体外活性测定,以期获得新的CCR5受体抑制剂的先导化合物。方法利用Discovery Studio 2.0软件构建HypoGen药效团模型;利用Sybyl-X 2.0软件构建Surflexdock分子对接模型;采用多级筛选的策略,运用"类药五原则"、药效团模型和分子对接模型对ZINC数据库进行逐级筛选;通过检测TZM-bl细胞中荧光素酶报告基因的表达情况来判断化合物的抗HIV-1活性,并通过MTT实验考查化合物的细胞毒性。结果成功构建了药效团和分子对接模型,并对ZINC数据库进行了多级虚拟筛选,得到6个待测化合物(B01-06);活性检测结果证实,B04的IC50为(29.52±3.73)μmol/L,CC50为(181.4±14.22)μmol/L;B06的IC50为(42.13±5.06)μmol/L,CC50为(354.9±28.82)μmol/L。结论化合物B04和B06具有一定的抗HIV-1活性,可作为潜在的先导化合物进行进一步的结构改造。
基金supported by the National Natural Science Foundation of China(Grant No.20902068)Natural Science Foundation of Inner Mongolia Autonomous Region,China(Grant No.2011BS1201)+1 种基金Program for Young Talents of ScienceTechnology in Universities of Inner Mongolia Autonomous Region,China
文摘Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis （Hypo2） including one hydrogen-bond donor （D）, one hydrogen-bond acceptor （A）, and two hydrophobic （H） features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.
基金National Natural Science Foundation of China(Grant No.81373272)
文摘Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.
基金Supported by the National Natural Science Foundation of China under Grant No. 10647112the Fundamental Research Funds for the Central Universities
文摘In this paper, we consider a system of （2＋2）-dimensional nonlinear models by using CK direct method and Hereman-Nuseir method generated by the Janlent-Miodek Hierarchy. We construct some new multiple kink and singular kink solutions of （2＋1）-Dimensional Nonlinear Models with the aid of symbolic computation.
