| Title | Docking field-based QSAR and pharmacophore studies on the substituted pyrimidine derivatives targeting HIV-1 reverse transcriptase |
| Authors | Fan, Ningning Zhang, Shuang Sheng, Tao Zhao, Liang Liu, Zhenming Liu, Junyi Wang, Xiaowei |
| Affiliation | Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Beijing, Peoples R China. Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China. Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Beijing, Peoples R China. Liu, ZM (reprint author), Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China. |
| Keywords | docking field-based QSAR NNRTI pharmacophores pyrimidine analogues BIOLOGICAL EVALUATION NONNUCLEOSIDE INHIBITORS DRUG-RESISTANCE COMPLEXES MECHANISM ANALOGS DESIGN SERIES SITE CURE |
| Issue Date | 2018 |
| Publisher | CHEMICAL BIOLOGY & DRUG DESIGN |
| Citation | CHEMICAL BIOLOGY & DRUG DESIGN. 2018, 91(2), 398-407. |
| Abstract | HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of .8078, cross-validated value of 0.5397 for training set and Q(2) of 0.4669, Pearson's r of .7357 for test set). Docking, pocket surfaces, and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) - interaction with residue Tyr181, Tyr188, and Trp229 and p- interaction with His235 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, and AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein-ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors. |
| URI | http://hdl.handle.net/20.500.11897/499853 |
| ISSN | 1747-0277 |
| DOI | 10.1111/cbdd.13086 |
| Indexed | SCI(E) PubMed Medline |
| Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 |
