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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow
Journal of medicinal chemistry, v 64(7), pp 3747-3766
08 Apr 2021
PMID: 33750123
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow
- Creators
- Megan E Meuser - Drexel UniversityPoli Adi Narayana Reddy - The Wistar InstituteAlexej Dick - Drexel UniversityJean Marc Maurancy - Drexel UniversityJoseph M Salvino - The Wistar InstituteSimon Cocklin - Drexel University
- Publication Details
- Journal of medicinal chemistry, v 64(7), pp 3747-3766
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R56 AI118415 / NIAID NIH HHS R01 NS089435 / NINDS NIH HHS R01 AI150491 / NIAID NIH HHS T32 MH079785 / NIMH NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000639043300013
- Scopus ID
- 2-s2.0-85104047340
- Other Identifier
- 991019168868604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal