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Eur J Med Chem. 2019 Sep 15;178:818-837. doi: 10.1016/j.ejmech.2019.06.020. Epub 2019 Jun 9.

The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

Author information

1
Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
2
ImQuest Biosciences, 7340 Executive Way, Suite R, Frederick, MD, 21704, USA.
3
Laboratory of Cell Biology, NCI, NIH, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
4
Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA. Electronic address: appellad@niddk.nih.gov.

Abstract

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol-thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.

KEYWORDS:

Activity limit; Antiviral; HIV; Mercaptobenzamide prodrug; Molecular dynamics; NCp7; SAMT

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