The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of ...The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of DAPY inhibitors and their binding mode. We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA, and 8 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross-validation and external validation were 0.979, 0.597 and 0.756, respectively. Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database(2012). Finally, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability. Topomer Search technology could be effectively used to screen and design new compound, and had good predictive capability to guide the design of new Anti-HIV drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the DAPY derivatives and MET230, TRP229, PHE227, TYR318, TYR183, PRO95, GLY99, ILE100,TYR188, VAL106, TYR181, GLY190, GLU138, VAL179, THR139, ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase. These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.展开更多
Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a s...Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.展开更多
基金supported by the National Natural Science Foundation of China(21475081,21275094)the Graduate Innovation Fund of Shaanxi University of Science and Technology
文摘The diarylpyrimidine(DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors. The present study is aimed at studying the three-dimensional quantitative structure-activity relationship(3D-QSAR) of DAPY inhibitors and their binding mode. We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA, and 8 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross-validation and external validation were 0.979, 0.597 and 0.756, respectively. Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database(2012). Finally, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability. Topomer Search technology could be effectively used to screen and design new compound, and had good predictive capability to guide the design of new Anti-HIV drugs. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the DAPY derivatives and MET230, TRP229, PHE227, TYR318, TYR183, PRO95, GLY99, ILE100,TYR188, VAL106, TYR181, GLY190, GLU138, VAL179, THR139, ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase. These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.81973181,82273773)Shandong Provincial Natural Science Foundation(Nos.ZR2020YQ61,ZR2020JQ31)Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province。
文摘Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.
