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Bioorg Med Chem. 2016 Oct 15;24(20):4768-4778. doi: 10.1016/j.bmc.2016.07.039. Epub 2016 Jul 21.

Computer-aided discovery of anti-HIV agents.

Author information

1
Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States. Electronic address: william.jorgensen@yale.edu.

Abstract

A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.

KEYWORDS:

Anti-HIV drugs; Free energy perturbation; NNRTIs; Structure-based design

PMID:
27485603
PMCID:
PMC5114837
DOI:
10.1016/j.bmc.2016.07.039
[Indexed for MEDLINE]
Free PMC Article

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