Identification of potential inhibitors of omicron variant of SARS-Cov-2 RBD based virtual screening, MD simulation, and DFT.
Identification of potential inhibitors of omicron variant of SARS-Cov-2 RBD based virtual screening, MD simulation, and DFT.
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基于虚拟筛选、MD 模拟和 DFT 鉴定 SARS-Cov-2 RBD omicron 变体的潜在抑制剂
DOI：
10.3389/fchem.2022.1063374
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
关注的SARS-CoV-2 Omicron变体（VOC; B.1.1.529）的出现导致COVID-19大流行的新高峰，这要求开发针对Omicron VOC的有效疗法。刺突蛋白的受体结合结构域（RBD）负责人ACE 2受体蛋白的识别和结合，是潜在的药物靶点。据推测，S蛋白受体结合结构域的突变可以增强Omicron VOC与宿主蛋白质的结合强度。在本研究中，进行生物信息学分析以筛选靶向omicron VOC的潜在治疗化合物。通过对接和结合自由能分析，基于S蛋白的受体结合结构域从不同文库中筛选出总共92，699个化合物，产生前5个最佳命中。采用动力学模拟轨迹分析和结合自由能分解方法，重点研究候选分子与受体结合域上识别残基的相互作用，确定候选分子的抑制机制。进行ADMET预测和DFT计算以确定所鉴定分子的药代动力学参数和精确化学性质。所鉴定的分子的分子特性及其通过受体结合结构域干扰人ACE 2受体识别的能力表明它们是SARS-CoV-2 Omicron VOC的潜在治疗剂。
Emergence of the SARS-CoV-2 Omicron variant of concern (VOC; B.1.1.529) resulted in a new peak of the COVID-19 pandemic, which called for development of effective therapeutics against the Omicron VOC. The receptor binding domain (RBD) of the spike protein, which is responsible for recognition and binding of the human ACE2 receptor protein, is a potential drug target. Mutations in receptor binding domain of the S-protein have been postulated to enhance the binding strength of the Omicron VOC to host proteins. In this study, bioinformatic analyses were performed to screen for potential therapeutic compounds targeting the omicron VOC. A total of 92,699 compounds were screened from different libraries based on receptor binding domain of the S-protein via docking and binding free energy analysis, yielding the top 5 best hits. Dynamic simulation trajectory analysis and binding free energy decomposition were used to determine the inhibitory mechanism of candidate molecules by focusing on their interactions with recognized residues on receptor binding domain. The ADMET prediction and DFT calculations were conducted to determine the pharmacokinetic parameters and precise chemical properties of the identified molecules. The molecular properties of the identified molecules and their ability to interfere with recognition of the human ACE2 receptors by receptor binding domain suggest that they are potential therapeutic agents for SARS-CoV-2 Omicron VOC.
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影响因子：
15
作者：
JOLAD, SD;HOFFMANN, JJ;KRIEK, GR
通讯作者：
KRIEK, GR
影响因子：
4.4
作者：
Di Remigio, Roberto;Mozgawa, Krzysztof;Frediani, Luca
通讯作者：
Frediani, Luca
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
4.4
作者：
DITCHFIELD, R;HEHRE, WJ;POPLE, JA
通讯作者：
POPLE, JA