Discovery of HIV-1 Integrase Inhibitors by Pharmacophore Searching

• Published in: Journal of medicinal chemistry 1997-03, Vol.40 (6), p.930-936
• Main Authors: Hong, Huixiao, Neamati, Nouri, Wang, Shaomeng, Nicklaus, Marc C, Mazumder, Abhijit, Zhao, He, Burke, Terrence R, Pommier, Yves, Milne, George W. A
• Format: Article
• Language: English
• Subjects: 4-Hydroxycoumarins - pharmacology; AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Computer Simulation; Databases, Factual; Drug Design; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - enzymology; Human immunodeficiency virus 1; Medical sciences; Models, Molecular; Molecular Structure; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - metabolism; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960754h

Based upon a class of known HIV-1 integrase inhibitors, several pharmacophore models were proposed from molecular modeling studies and validated using a 3D database of 152 compounds for which integrase assay data are known. Using the most probable pharmacophore model as the query, the NCI 3D database of 206 876 compounds was searched, and 340 compounds that contain the pharmacophore query were identified. Twenty-nine of these compounds were selected and tested in the HIV-1 integrase assay. This led to the discovery of 10 novel, structurally diverse HIV-1 integrase inhibitors, four of which have an IC50 value less than 30 μM and are promising lead compounds for further HIV-1 integrase inhibitor development.