Investigating how HIV-1 antiretrovirals differentially behave as substrates and inhibitors of P-glycoprotein via molecular dynamics simulations
HIV-1 can rapidly infect the brain upon initial infection, establishing latent reservoirs that induce neuronal damage and/or death, resulting in HIV-Associated Neurocognitive Disorder. Though anti-HIV-1 antiretrovirals (ARVs) suppress viral load, the blood-brain barrier limits drug access to the bra...
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Published in: | Computational and structural biotechnology journal Vol. 23; pp. 2669 - 2679 |
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Main Authors: | , , , |
Format: | Journal Article |
Language: | English |
Published: |
Netherlands
Elsevier B.V
01-12-2024
Research Network of Computational and Structural Biotechnology Elsevier |
Subjects: | |
Online Access: | Get full text |
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Summary: | HIV-1 can rapidly infect the brain upon initial infection, establishing latent reservoirs that induce neuronal damage and/or death, resulting in HIV-Associated Neurocognitive Disorder. Though anti-HIV-1 antiretrovirals (ARVs) suppress viral load, the blood-brain barrier limits drug access to the brain, largely because of highly expressed efflux proteins like P-glycoprotein (P-gp). While no FDA-approved P-gp inhibitor currently exists, HIV-1 protease inhibitors show promise as partial P-gp inhibitors, potentially enhancing drug delivery to the brain. Herein, we employed docking and molecular dynamics simulations to elucidate key differences in P-gp’s interactions with several antiretrovirals, including protease inhibitors, with known inhibitory or substrate-like behaviors towards P-gp. Our results led us to hypothesize new mechanistic details of small-molecule efflux by and inhibition of P-gp, where the “Lower Pocket” in P-gp’s transmembrane domain serves as the primary initial site for small-molecule binding. Subsequently, this pocket merges with the more traditionally studied drug binding site—the “Upper Pocket”—thus funneling small-molecule drugs, such as ARVs, towards the Upper Pocket for efflux. Furthermore, our results reinforce the understanding that both binding energetics and changes in protein dynamics are crucial in discerning small molecules as non-substrates, substrates, or inhibitors of P-gp. Our findings indicate that interactions between P-gp and inhibitory ARVs induce bridging of transmembrane domain helices, impeding P-gp conformational changes and contributing to the inhibitory behavior of these ARVs. Overall, insights gained in this study could serve to guide the design of future P-gp-targeting therapeutics for a wide range of pathological conditions and diseases, including HIV-1.
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2001-0370 2001-0370 |
DOI: | 10.1016/j.csbj.2024.06.025 |