Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research Kolkata, Maniktala Main Road, 700054, Kolkata, WB, India.
Discipline of Natural Sciences, Indian Institute of Information Technology, Design, and Manufacturing, Dumna Airport Road, Jabalpur-482005, India.
Eur J Pharm Sci. 2021 Dec 1;167:106012. doi: 10.1016/j.ejps.2021.106012. Epub 2021 Sep 17.
The rapid proliferation of SARS-CoV-2 in COVID-19 patients has become detrimental to their lives. However, blocking the replication cycle of SARS-CoV-2 will help in suppressing the viral loads in patients, which would ultimately help in the early recovery. To discover such drugs, molecular docking, MD-simulations, and MM/GBSA approaches have been used herein to examine the role of several short ionic peptides in inhibiting the RNA binding site of the RNA-dependent RNA polymerase (RdRp). Out of the 49 tri- and tetrapeptide inhibitors studied, 8 inhibitors were found to bind RdRp strongly as revealed by the docking studies. Among these inhibitors, the Ala1-Arg2-Lys3-Asp4 and Ala1-Lys2-Lys3-Asp4 are found to make the most stable complexes with RdRp and possess the ΔG of -17.41 and -14.21 kcal/mol respectively as revealed by the MD and MM/GBSA studies. Hence these peptide inhibitors would be highly potent in inhibiting the activities of RdRp. It is further found that these inhibitors can occupy the positions of the nucleotide triphosphate (NTP) insertion site, thereby inhibiting the replication of the viral genome by obstructing the synthesis of new nucleotides. Structural and energetic comparisons of these inhibitors with Remdesivir and similar nucleotide drugs show that these peptides would be more specific and hence may act as promiscuous antiviral agents against RdRp.
SARS-CoV-2 在 COVID-19 患者中的快速增殖对他们的生命造成了危害。然而，阻断 SARS-CoV-2 的复制周期将有助于抑制患者体内的病毒载量，这最终有助于早期康复。为了发现此类药物，本文使用分子对接、MD 模拟和 MM/GBSA 方法来研究几种短离子肽在抑制 RNA 依赖性 RNA 聚合酶（RdRp）的 RNA 结合位点中的作用。在所研究的 49 种三肽和四肽抑制剂中，有 8 种抑制剂通过对接研究被发现强烈结合 RdRp。在这些抑制剂中，Ala1-Arg2-Lys3-Asp4 和 Ala1-Lys2-Lys3-Asp4 与 RdRp 形成最稳定的复合物，通过 MD 和 MM/GBSA 研究分别显示 ΔG 为-17.41 和-14.21 kcal/mol。因此，这些肽抑制剂将非常有效地抑制 RdRp 的活性。进一步发现，这些抑制剂可以占据核苷酸三磷酸（NTP）插入位点，从而通过阻止新核苷酸的合成来阻碍病毒基因组的复制。这些抑制剂与瑞德西韦和类似核苷酸药物的结构和能量比较表明，这些肽将更加特异，因此可能作为针对 RdRp 的广谱抗病毒药物。
