Virtual screening application of a model of full-length HIV-1 integrase complexed with viral DNA.
To address the absence of experimental data on the full-length structure of HIV-1 integrase and the way it binds to viral and human DNA, we had previously [Karki, R. G.; Tang, Y.; Burke, T. R., Jr.; Nicklaus, M. C. J. Comput. Aided Mol. Des.2004, 18, 739] constructed models of full-length HIV-1 integrase complexed with models of viral and human DNA. Here we describe the discovery of novel HIV-1 integrase strand transfer inhibitors based on one of these models. Virtual screening methods including docking and filtering by predicted ADME/Tox properties yielded several microM level inhibitors of the strand transfer reaction catalyzed by wild-type HIV-1 integrase.
Liao
Chenzhong
C
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, USA.
Karki
Rajeshri G
RG
Marchand
Christophe
C
Pommier
Yves
Y
Nicklaus
Marc C
MC
D002384:Catalysis; D004279:DNA, Viral / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase