Gurung Arun Bahadur, Ali Mohammad Ajmal, Lee Joongku, Farah Mohammad Abul, Al-Anazi Khalid Mashay, Sami Hiba
Department of Basic Sciences and Social Sciences, North-Eastern Hill University, Shillong 793022, Meghalaya, India.
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
Saudi J Biol Sci. 2022 Jan;29(1):53-64. doi: 10.1016/j.sjbs.2021.09.042. Epub 2021 Sep 17.
Human serum albumin (HSA) is the most prevalent protein in the blood plasma which binds an array of exogenous compounds. Drug binding to HSA is an important consideration when developing new therapeutic molecules, and it also aids in understanding the underlying mechanisms that govern their pharmacological effects. This study aims to investigate the molecular binding of coronavirus disease 2019 (COVID-19) therapeutic candidate molecules to HSA and to identify their putative binding sites. Binding energies and interacting residues were used to evaluate the molecular interaction. Four drug candidate molecules (β-D-N4-hydroxycytidine, Chloroquine, Disulfiram, and Carmofur) demonstrate weak binding to HSA, with binding energies ranging from -5 to -6.7 kcal/mol. Ivermectin, Hydroxychloroquine, Remdesivir, Arbidol, and other twenty drug molecules with binding energies ranging from -6.9 to -9.5 kcal/mol demonstrated moderate binding to HSA. The strong HSA binding drug candidates consist of fourteen molecules (Saquinavir, Ritonavir, Dihydroergotamine, Daclatasvir, Paritaprevir etc.) with binding energies ranging from -9.7 to -12.1 kcal/mol. All these molecules bind to different HSA subdomains (IA, IB, IIA, IIB, IIIA, and IIIB) through molecular forces such as hydrogen bonds and hydrophobic interactions. Various pharmacokinetic properties (gastrointestinal absorption, blood-brain barrier permeation, P-glycoprotein substrate, and cytochrome P450 inhibitor) of each molecule were determined using SwissADME program. Further, the stability of the HSA-ligand complexes was analyzed through 100 ns molecular dynamics simulations considering various geometric properties. The binding free energy between free HSA and compounds were calculated using Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) approach. The findings of this study might be useful in understanding the mechanism of COVID-19 drug candidates binding to serum albumin protein, as well as their pharmacodynamics and pharmacokinetics.
人血清白蛋白（HSA）是血浆中最普遍的蛋白质，它能结合一系列外源性化合物。在开发新的治疗分子时，药物与HSA的结合是一个重要的考虑因素，它也有助于理解控制其药理作用的潜在机制。本研究旨在研究2019冠状病毒病（COVID-19）治疗候选分子与HSA的分子结合，并确定它们的假定结合位点。结合能和相互作用残基用于评估分子相互作用。四种候选药物分子（β-D-N4-羟基胞苷、氯喹、双硫仑和卡莫氟）与HSA的结合较弱，结合能范围为-5至-6.7千卡/摩尔。伊维菌素、羟氯喹、瑞德西韦、阿比多尔和其他20种结合能范围为-6.9至-9.5千卡/摩尔的药物分子与HSA表现出中等程度的结合。与HSA结合较强的候选药物由14种分子（沙奎那韦、利托那韦、双氢麦角胺、达卡他韦、帕立普韦等）组成，结合能范围为-9.7至-12.1千卡/摩尔。所有这些分子通过氢键和疏水相互作用等分子力与不同的HSA亚结构域（IA、IB、IIA、IIB、IIIA和IIIB）结合。使用SwissADME程序测定了每个分子的各种药代动力学性质（胃肠道吸收、血脑屏障通透性、P-糖蛋白底物和细胞色素P450抑制剂）。此外，通过考虑各种几何性质的100纳秒分子动力学模拟分析了HSA-配体复合物的稳定性。使用分子力学泊松-玻尔兹曼表面积（MM/PBSA）和分子力学广义玻恩表面积（MM/GBSA）方法计算游离HSA与化合物之间的结合自由能。本研究的结果可能有助于理解COVID-19候选药物与血清白蛋白结合的机制，以及它们的药效学和药代动力学。
