PDF(Pubmed)
Abstract：
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.
摘要：
HIV-1在初次感染时可以迅速感染大脑，建立诱发神经元损伤和/或死亡的潜在储库，导致HIV相关神经认知障碍。虽然抗HIV-1抗逆转录病毒药物（ARVs）抑制病毒载量，血脑屏障限制药物进入大脑,主要是因为高表达的外排蛋白，如P-糖蛋白（P-gp）。虽然目前没有FDA批准的P-gp抑制剂存在，HIV-1蛋白酶抑制剂有望作为部分P-gp抑制剂，可能会增强药物向大脑的输送。在这里，我们采用对接和分子动力学模拟来阐明P-gp与几种抗逆转录病毒药物相互作用的关键差异，包括蛋白酶抑制剂,对P-gp具有已知的抑制或底物样行为。我们的结果使我们假设小分子外排和抑制P-gp的新机理细节，其中P-gp跨膜结构域中的“下口袋”作为小分子结合的主要初始位点。随后，这个口袋与更传统研究的药物结合位点——“上口袋”——因此汇集了小分子药物，比如抗逆转录病毒药物，朝向上层口袋外排。此外，我们的结果加强了这样的认识，即结合能量学和蛋白质动力学的变化对于将小分子识别为非底物至关重要，基材,或P-gp的抑制剂。我们的发现表明，P-gp和抑制性ARV之间的相互作用诱导跨膜结构域螺旋的桥接，阻碍P-gp构象变化并有助于这些ARV的抑制行为。总的来说,在这项研究中获得的见解可以指导未来的P-gp靶向疗法的设计，以治疗广泛的病理状况和疾病，包括HIV-1。
