Graduate Program in Medicinal Chemistry and Molecular Modeling, Federal University of Pará, Belem 66075-110, PA, Brazil.
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapa 68903-419, AP, Brazil.
Int J Mol Sci. 2023 May 16;24(10):8814. doi: 10.3390/ijms24108814.
When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts' angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein's crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of -8.645 kcal·mol, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.
当 2019 年 12 月中国武汉市爆发疫情时，冠状病毒被确定为病因。病毒感染是通过病毒 S 蛋白与宿主血管紧张素转换酶 2 的相互作用发生的。本研究利用 DrugBank 数据库和生物信息学技术等资源，设计并鉴定了针对 SARS-CoV-2 刺突蛋白的潜在活性配体。使用 FTMap 服务器和 Molegro 软件确定了 Spike-ACE2 蛋白晶体结构的活性部位。使用从抗寄生虫药物获得的药效团模型对虚拟筛选进行了研究，从 molport 获得了 2000 个分子。利用 ADME/Tox 概况来识别具有理想药物特性的最有前途的化合物。然后对选定的候选物进行了结合亲和力研究。分子对接研究表明，有五个结构的结合亲和力优于羟氯喹。配体_003 的结合亲和力为-8.645 kcal·mol，被认为是该研究的最佳值。配体_033、配体_013、配体_044 和配体_080 的值符合新型药物的特征。为了选择具有良好合成潜力的化合物，进行了合成可及性研究和相似性分析。分子动力学和理论 IC 值（范围为 0.459 至 2.371 µM）表明，这些候选物具有进一步测试的潜力。化学描述符表明候选物具有很强的分子稳定性。这里的理论分析表明，这些分子具有作为 SARS-CoV-2 抗病毒药物的潜力，因此值得进一步研究。
