Computational Analysis of Interactions Between Drugs and Human Serum Albumin

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Muslum Yildiz
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引用次数: 0

Abstract

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.

Abstract Image

药物与人血清白蛋白相互作用的计算分析
药物分子以与血清蛋白(如人血清白蛋白(HSA))络合和/或未结合的游离形式存在于血液循环中。药物只有在游离状态下才能发挥作用。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。本研究对 2990 种经 FDA 批准的药物与 HSA 之间的相互作用进行了计算分析,以揭示药物与 HSA 相互作用的关键原理。对接结果显示,药物对空腔-1(C1)的亲和力高于空腔-2(C2)。共有 1131 个药物分子的对接得分大于 60 分,而 768 个药物分子对接 C2 时的对接得分大于 60 分。此外,有三个溶剂通道有可能将溶剂导向 C1 腔,而 C2 没有任何有效通道。MD 后分析表明,药物在结合腔中与碱性氨基酸发生极性相互作用。在整个 MD 模拟过程中,马鞭草苷和头孢他啶都具有稳定的低 RMSD 值,在 C1 腔中平均为 2 Å。动词苷的配体 RMSD 值稳定性较差,在 C1 中与 HSA 复合物时约为 4 Å。残基 K192、K196、R215 和 R254 对头孢他啶的贡献分别为 -1.92 ± 0.18、-3.09 ± 0.09、-2.17 ± 0.17 和 - 2.32 ± 0.098。这些残基在 C1 腔中对动词苷结合能的贡献分别为 -6.06 ± 0.08、-2.10 ± 0.06 和 - 1.57 ± 0.03 kcal/mol。C2 通过 R469、K472 和 K488 残基与药物发生极性相互作用,它们对头孢他啶总结合能的贡献分别为 R469 -3.13 ± 0.21 kcal/mol、K472 -1.94 ± 0.18 kcal/mol 和 K488 -1.96 ± 0.11 kcal/mol。动词苷的结合能为 57.17 ± 7.00 kcal/mol,其中 Arg-407 的单独结合能贡献最大,为 -4.29 ± 0.12 kcal/mol。具有氢键供体/受体化学加合物的药物(如动词苷)在 C1 袋中形成的氢键较多。头孢他啶与 HSA 相互作用的方向是 C2 腔中的疏水残基 L384、L404、L487 和 L488。
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来源期刊
Journal of Molecular Recognition
Journal of Molecular Recognition 生物-生化与分子生物学
CiteScore
4.60
自引率
3.70%
发文量
68
审稿时长
2.7 months
期刊介绍: Journal of Molecular Recognition (JMR) publishes original research papers and reviews describing substantial advances in our understanding of molecular recognition phenomena in life sciences, covering all aspects from biochemistry, molecular biology, medicine, and biophysics. The research may employ experimental, theoretical and/or computational approaches. The focus of the journal is on recognition phenomena involving biomolecules and their biological / biochemical partners rather than on the recognition of metal ions or inorganic compounds. Molecular recognition involves non-covalent specific interactions between two or more biological molecules, molecular aggregates, cellular modules or organelles, as exemplified by receptor-ligand, antigen-antibody, nucleic acid-protein, sugar-lectin, to mention just a few of the possible interactions. The journal invites manuscripts that aim to achieve a complete description of molecular recognition mechanisms between well-characterized biomolecules in terms of structure, dynamics and biological activity. Such studies may help the future development of new drugs and vaccines, although the experimental testing of new drugs and vaccines falls outside the scope of the journal. Manuscripts that describe the application of standard approaches and techniques to design or model new molecular entities or to describe interactions between biomolecules, but do not provide new insights into molecular recognition processes will not be considered. Similarly, manuscripts involving biomolecules uncharacterized at the sequence level (e.g. calf thymus DNA) will not be considered.
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