title: Discovery of HIV-1 integrase inhibitors: pharmacophore mapping, virtual screening, molecular docking, synthesis, and biological evaluation.
abstract: HIV-1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV-1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q(fit) value were used to design 30 molecules bearing pteridine ring and were docked on co-crystal structure of HIV-1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave-assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti-HIV activity against the replication of HIV-1 (IIIB) in MT-4 cells. The used approach of molecular docking and anti-HIV activity data of designed molecules will provide significant insights to discover novel HIV-1 Integrase Inhibitors.
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, India.
authors: Hardik
authors: H
authors: Bhatt
authors: Paresh
authors: P
authors: Patel
authors: Christophe
authors: C
authors: Pannecouque
mesh_terms: D019540:Area Under Curve; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D016208:Databases, Factual; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011621:Pteridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012372:ROC Curve; D012984:Software; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D011621:Pteridines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: HIV-1 integrase; Tripos; molecular docking; pharmacophore mapping; pteridin; virtual screening