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Computer-aided discovery of anti-HIV agents.

Computer-aided discovery of anti-HIV agents.
Author Information (click to view)

Jorgensen WL,


Jorgensen WL, (click to view)

Jorgensen WL,

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Bioorganic & medicinal chemistry 2016 Jul 2124(20) 4768-4778 pii 10.1016/j.bmc.2016.07.039

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.

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