Ligand-based design, molecular dynamics and ADMET studies of suggested SARS-CoV-2 Mpro inhibitors,RSC Advances

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Ligand-based design, molecular dynamics and ADMET studies of suggested SARS-CoV-2 Mpro inhibitors
RSC Advances ( IF 3.9 ) Pub Date : 2021-1-22 , DOI: 10.1039/d0ra10141a
Nada M Mohamed ₁ , Eslam M H Ali _{1,

2} , Asmaa M AboulMagd ₃

Affiliation

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been the choice of recent studies worldwide to control its pandemic. Given the similarity with the earlier SARS-CoV, it is possible to use the previously reported inhibitors to develop a new treatment for the current attack of SARS-CoV-2. This study used the formerly published SARS-CoV M^pro small-molecule protease inhibitors to develop a pharmacophore model in order to design new ligands. Several strategies and scaffolds were evaluated in silico giving rise to ten newly designed compounds. Molecular docking and dynamics simulations were performed on M^pro enzyme in its active site to evaluate the newly designed ligands I–X. The results obtained from this work showed that compounds III–VI had a better molecular docking score than the co-crystallized ligand baicalein (3WL) giving −5.99, −5.94, −6.31, −6.56 and −5.74 kcal mol⁻¹, respectively. Moreover, they could bind to the M^pro binding site better than I, II and VII–X. The most promising chromen-2-one based compounds V–VI had sufficiently acceptable physicochemical and ADMET properties to be considered new leads for further investigations. This new understanding should help to improve predictions of the impact of new treatments on COVID-19.

中文翻译：

建议的 SARS-CoV-2 Mpro 抑制剂的基于配体的设计、分子动力学和 ADMET 研究

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 已成为全球最近研究控制其大流行的选择。鉴于与早期 SARS-CoV 的相似性，有可能使用先前报道的抑制剂来开发针对当前 SARS-CoV-2 攻击的新疗法。本研究使用之前发表的 SARS-CoV M ^pro小分子蛋白酶抑制剂开发了药效团模型，以设计新的配体。在计算机上评估了几种策略和支架，产生了十种新设计的化合物。对 M ^pro酶的活性位点进行分子对接和动力学模拟，以评估新设计的配体I-X. 从这项工作获得的结果表明，化合物III-VI具有比共结晶配体黄芩素 (3WL) 更好的分子对接分数，分别为 -5.99、-5.94、-6.31、-6.56 和 -5.74 kcal mol ^-1。此外，它们可以比I、II和VII-X更好地与 M ^pro结合位点结合。最有希望的基于 chromen-2-one 的化合物V-VI具有足够可接受的物理化学和 ADMET 特性，被认为是进一步研究的新线索。这种新的理解应该有助于改进对新疗法对 COVID-19 影响的预测。

更新日期：2021-01-22

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