Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey.
J Mol Recognit. 2024 Nov;37(6):e3105. doi: 10.1002/jmr.3105. Epub 2024 Sep 21.
Drug molecules exist as complexed with serum proteins such as human serum albumin (HSA) and/or unbound free form in the blood circulation. Drugs can be effective only when they are free. Thus, it is important to understand aspects that are important for interaction between drugs and interacting proteins. In this study, interactions among 2990 FDA approved drugs and HSA were computational analyzed to unravel principles that are critical for drug-HSA interactions. Docking results showed that drugs have higher affinity toward cavity-1 (C1) than cavity-2 (C2). A total of 1131 drug molecules have docking score greater than 60 while 768 molecules have docking score greater than 60 when they are docked in C2. In addition, three solvent channels have potential to direct solvent to C1 cavity while C2 does not have any effective channel. The post MD analyses demonstrated that drugs are making polar interactions with basic amino acids in the binding cavities. Verbscoside and ceftazidime both have stable low RMSD values throughout MD simulation with 2 Å on average in C1 cavity. The ligand RMSD shows less stability for verbscoside, which is around 4 Å when it is in complex with HSA in C1. The individual contribution of the residues K192, K196, R215, and R254 to ceftazidime are -1.92 ± 0.18, -3.09 ± 0.09, -2.17 ± 0.17, and - 2.32 ± 0.098, respectively. These residues contribute the binding energy of the verbscoside by -6.06 ± 0.08, -2.10 ± 0.06, and - 1.57 ± 0.03 kcal/mol individually in C1 cavity. C2 is making polar interactions with drug via R469, K472, and K488 residues and their contribution to the two drugs are -3.13 ± 0.21 kcal/mol for R469, -1.94 ± 0.18 kcal/mol for K472, and -1.96 ± 0.11 kcal/mol for K488 to total binding energy of ceftazidime. The binding energy of verbscoside is 57.17 ± 7.00 kcal/mol and Arg-407 has the highest contribution this bind energy individually with -4.29 ± 0.12 kcal/mol. Drugs with hydrogen bond donor/acceptor chemical adducts such as verbscoside involve higher hydrogen bond formation in C1 pocket. Ceftazidime makes interaction with HSA toward hydrophobic residues, L384, L404, L487, and L488 in the C2 cavity.
药物分子与血清蛋白（如人血清白蛋白（HSA））形成复合物，并以游离的未结合形式存在于血液循环中。只有当药物处于游离状态时，才能发挥作用。因此，了解药物与相互作用蛋白之间相互作用的重要方面非常重要。在这项研究中，对 2990 种 FDA 批准的药物与 HSA 之间的相互作用进行了计算分析，以揭示药物-HSA 相互作用的关键原则。对接结果表明，药物与腔 1（C1）的亲和力高于腔 2（C2）。当药物在 C2 中对接时，有 1131 个药物分子的对接评分大于 60，而有 768 个药物分子的对接评分大于 60。此外，有三个溶剂通道有可能将溶剂引导到 C1 腔，而 C2 没有任何有效的通道。MD 分析后表明，药物与结合腔中的碱性氨基酸发生极性相互作用。毛蕊花糖苷和头孢他啶在整个 MD 模拟中均具有稳定的低 RMSD 值，平均在 C1 腔中为 2Å。配体 RMSD 显示毛蕊花糖苷的稳定性较差，当它与 HSA 结合在 C1 中时，其 RMSD 值约为 4Å。残基 K192、K196、R215 和 R254 对头孢他啶的个体贡献分别为-1.92±0.18、-3.09±0.09、-2.17±0.17 和-2.32±0.098。这些残基分别使毛蕊花糖苷的结合能降低了-6.06±0.08、-2.10±0.06 和-1.57±0.03 kcal/mol。C2 通过残基 R469、K472 和 K488 与药物发生极性相互作用，其对两种药物的贡献分别为头孢他啶的-3.13±0.21 kcal/mol、K472 的-1.94±0.18 kcal/mol和 K488 的-1.96±0.11 kcal/mol，总计为头孢他啶的结合能。毛蕊花糖苷的结合能为 57.17±7.00 kcal/mol，Arg-407 对该结合能的贡献最大，为-4.29±0.12 kcal/mol。具有氢键供体/受体化学加合物的药物，如毛蕊花糖苷，在 C1 口袋中形成更高的氢键。头孢他啶与 HSA 相互作用，在 C2 腔中与疏水性残基 L384、L404、L487 和 L488 相互作用。
