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Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow
Journal article   Open access   Peer reviewed

Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow

Megan E Meuser, Poli Adi Narayana Reddy, Alexej Dick, Jean Marc Maurancy, Joseph M Salvino and Simon Cocklin
Journal of medicinal chemistry, v 64(7), pp 3747-3766
08 Apr 2021
DOI: https://doi.org/10.1021/acs.jmedchem.0c01810
PMID: 33750123
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043142View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Amino Acid Sequence Anti-HIV Agents - chemistry Anti-HIV Agents - metabolism Anti-HIV Agents - pharmacology Binding Sites Capsid Proteins - antagonists & inhibitors Capsid Proteins - chemistry Capsid Proteins - metabolism Cell Line, Tumor HEK293 Cells HIV-1 - drug effects Humans Indoles - chemistry Indoles - metabolism Indoles - pharmacology Microbial Sensitivity Tests Microsomes, Liver - metabolism Molecular Docking Simulation Protein Binding Protein Stability Stereoisomerism Workflow
Poor metabolic stability of the human immunodeficiency virus type-1 (HIV-1) capsid (CA) inhibitor is a major concern in its development toward clinical use. To improve on the metabolic stability, we employed a novel multistep computationally driven workflow, which facilitated the rapid design of improved analogs in an efficient manner. Using this workflow, we designed three compounds that interact specifically with the CA interprotomer pocket, inhibit HIV-1 infection, and demonstrate enantiomeric preference. Moreover, using this workflow, we were able to increase the metabolic stability 204-fold in comparison to in only three analog steps. These results demonstrate our ability to rapidly design CA compounds using a novel computational workflow that has improved metabolic stability over the parental compound. This workflow can be further applied to the redesign of and other promising inhibitors with a stability shortfall.

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10 Record Views
17 citations in Web of Science
18 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Chemistry, Medicinal
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