Molecular Diversity ( IF 3.9 ) Pub Date : 2020-10-20 , DOI: 10.1007/s11030-020-10148-5 Hemlata Pundir 1 , Tanuja Joshi 2 , Tushar Joshi 3 , Priyanka Sharma 1 , Shalini Mathpal 3 , Subhash Chandra 2, 4 , Sushma Tamta 1
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Abstract
Recently emerged SARS-CoV-2 is the cause of the ongoing outbreak of COVID-19. It is responsible for the deaths of millions of people and has caused global economic and social disruption. The numbers of COVID-19 cases are increasing exponentially across the world. Control of this pandemic disease is challenging because there is no effective drug or vaccine available against this virus and this situation demands an urgent need for the development of anti-SARS-CoV-2 potential medicines. In this regard, the main protease (Mpro) has emerged as an essential drug target as it plays a vital role in virus replication and transcription. In this research, we have identified two novel potent inhibitors of the Mpro (PubChem3408741 and PubChem4167619) from PubChem database by pharmacophore-based high-throughput virtual screening. The molecular docking, toxicity, and pharmacophore analysis indicate that these compounds may act as potential anti-viral candidates. The molecular dynamic simulation along with the binding free energy calculation by MMPBSA showed that these compounds bind to Mpro enzyme with high stability over 50 ns. Our results showed that two compounds: PubChem3408741 and PubChem4167619 had the binding free energy of − 94.02 kJ mol−1 and − 122.75 kJ mol−1, respectively, as compared to reference X77 (− 76.48 kJ mol−1). Based on our work’s findings, we propose that these compounds can be considered as lead molecules for targeting Mpro enzyme and they can be potential SARS-CoV-2 inhibitors. These inhibitors could be tested in vitro and explored for effective drug development against COVID-19.
Graphic abstract
中文翻译：
使用 Chou 的 5 步规则研究基于药效团的 SARS-CoV-2 Mpro 抑制剂虚拟筛选
摘要
最近出现的 SARS-CoV-2 是导致 COVID-19 持续爆发的原因。它要对数百万人的死亡负责，并造成全球经济和社会混乱。全球 COVID-19 病例的数量呈指数增长。控制这种大流行性疾病具有挑战性，因为没有针对这种病毒的有效药物或疫苗，这种情况迫切需要开发抗 SARS-CoV-2 的潜在药物。在这方面，主要蛋白酶（Mpro）已成为一种重要的药物靶标，因为它在病毒复制和转录中起着至关重要的作用。在这项研究中，我们通过基于药效团的高通量虚拟筛选从 PubChem 数据库中鉴定了两种新型的 Mpro 强效抑制剂（PubChem3408741 和 PubChem4167619）。分子对接、毒性、药效团分析表明这些化合物可能作为潜在的抗病毒候选物。分子动力学模拟以及 MMPBSA 的结合自由能计算表明，这些化合物与 Mpro 酶的结合稳定性超过 50 ns。我们的结果表明，两种化合物：PubChem3408741 和 PubChem4167619 的结合自由能为 - 94.02 kJ mol与参考 X77 (- 76.48 kJ mol -1 )相比，分别为-1和 - 122.75 kJ mol -1。根据我们的工作发现，我们建议这些化合物可以被认为是靶向 Mpro 酶的先导分子，它们可以成为潜在的 SARS-CoV-2 抑制剂。这些抑制剂可以在体外进行测试，并探索针对 COVID-19 的有效药物开发。
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