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，它与一系列外源性化合物结合。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，它还有助于了解控制其药理作用的潜在机制。本研究旨在调查 2019 冠状病毒病 (COVID-19) 治疗候选分子与 HSA 的分子结合，并确定其假定的结合位点。结合能和相互作用的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 kcal/mol。伊维菌素、羟氯喹、瑞德西韦、阿比朵尔、和其他 20 种结合能范围为 -6.9 至 -9.5 kcal/mol 的药物分子表现出与 HSA 的中等结合。强 HSA 结合候选药物由 14 种分子（沙奎那韦、利托那韦、二氢麦角胺、达卡他韦、Paritaprevir 等）组成，结合能范围为 -9.7 至 -12.1 kcal/mol。所有这些分子都通过氢键和疏水相互作用等分子力与不同的 HSA 子结构域（IA、IB、IIA、IIB、IIIA 和 IIIB）结合。使用 SwissADME 程序确定每个分子的各种药代动力学特性（胃肠道吸收、血脑屏障渗透、P-糖蛋白底物和细胞色素 P450 抑制剂）。此外，考虑到各种几何特性，通过 100 ns 分子动力学模拟分析了 HSA-配体复合物的稳定性。 这项研究的结果可能有助于了解 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。