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Thesis
An investigation into the binding mode of novel small molecule HIV-1 capsid (CA) protein inhibitors
Master of Science (M.S.), Drexel University
Jun 2020
DOI:
https://doi.org/10.17918/00000736
Abstract
Among the HIV-1 capsid inhibitors, PF-74 is by far the most characterized. It has a multimodal mechanism of action, preventing the uncoating of the capsid core and competitively inhibiting the interaction of the host dependency factors, such as CPSF6, by binding at an interprotomer pocket in the HIV-1 CA hexamer. Despite these attractive features, we have previously shown this inhibitor to have inferior metabolic stability, along with a relatively low potency. Using a multistep computational workflow, our group has designed three new analogs of PF-74 with much improved metabolic stability over the parental compound. To gain an understanding of the interaction of these compounds, including PF-74, within the interprotomer pocket of HIV-1 CA hexamer, we coupled docking analysis with mutagenesis and direct binding studies. Using this strategy, we identified a cluster of hydrophobic residues that contributed to the interaction of these compounds within the interprotomer pocket. Surface plasmon resonance (SPR) direct binding analyses of these compounds to the mutant CA hexameric proteins concluded that residues N57, M66, and K70 contributed the most binding energy to the interaction of these compounds in the CA-interprotomer pocket. In contrast, mutagenesis of residues L56, L69, I73 to N74, and N53 had only a marginal effect upon the binding of the compounds. Taken together, these results validate our docking models and provide vital information that can be used to optimize these compounds in terms of potency.
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Details
- Title
- An investigation into the binding mode of novel small molecule HIV-1 capsid (CA) protein inhibitors
- Creators
- Jean Marc Maurancy
- Contributors
- Simon Cocklin (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 45 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014695234104721