Computer-aided discovery of anti-HIV agents
- Bioorg Med Chem. 2016 Oct 15;24(20):4768-4778. doi: 10.1016/j.bmc.2016.07.039.
- 1. Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States. Electronic address: [email protected].
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.