CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, ...CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.展开更多
The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells,and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs.Highly...The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells,and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs.Highly active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of infection.In this study,HQSAR and Topomer Co MFA methods were used to establish QSAR models for 75 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives,and cross-validation and non-cross-validation were performed on the generated models.Two models with good statistical parameters and reliable prediction capabilities are obtained:(Topomer Co MFA:q2 = 0.687,r2 = 0.868,r2 pred = 0.623;HQSAR:q2 = 0.781,r2 = 0.921,r2 pred = 0.636).Contour maps and color code maps provide a lot of useful information for determining structural requirements that affect activity.Topomer search technology was used for virtual screening and molecular design.Surfex-dock method and ADMET technology were used to conduct molecular docking,oral bioavailability and toxicity prediction of the designed drug molecules.Results showed that A/ASN425,A/GLY198 and A/TRP427 may be the potential active residues of CCR5 inhibitors evaluated in this study,with 40 newly designed 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives which have the main ADMET properties and can be used as a reliable anti-HIV inhibitor.These results provide a certain theoretical basis for the experimental verification of new compounds in the future.展开更多
文摘CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.
基金supported by Innovation Supporting Plan of Shaanxi Province—Innovation Research Team (2018TD-015)the Natural Science Foundation of Shaanxi Province (2019JM-237)the Graduate Innovation Fund of Shaanxi University of Science and Technology。
文摘The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells,and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs.Highly active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of infection.In this study,HQSAR and Topomer Co MFA methods were used to establish QSAR models for 75 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives,and cross-validation and non-cross-validation were performed on the generated models.Two models with good statistical parameters and reliable prediction capabilities are obtained:(Topomer Co MFA:q2 = 0.687,r2 = 0.868,r2 pred = 0.623;HQSAR:q2 = 0.781,r2 = 0.921,r2 pred = 0.636).Contour maps and color code maps provide a lot of useful information for determining structural requirements that affect activity.Topomer search technology was used for virtual screening and molecular design.Surfex-dock method and ADMET technology were used to conduct molecular docking,oral bioavailability and toxicity prediction of the designed drug molecules.Results showed that A/ASN425,A/GLY198 and A/TRP427 may be the potential active residues of CCR5 inhibitors evaluated in this study,with 40 newly designed 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives which have the main ADMET properties and can be used as a reliable anti-HIV inhibitor.These results provide a certain theoretical basis for the experimental verification of new compounds in the future.
