Remdesivir-bound and ligand-free simulations reveal the probable mechanism of inhibiting the RNA dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2.
Remdesivir-bound and ligand-free simulations reveal the probable mechanism of inhibiting the RNA dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2.
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过去几个月，开发针对当前全球大流行COVID-19的潜在药物的努力有所增加。针对严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）的RNA依赖性RNA聚合酶（RdRP）的药物开发策略正在全球范围内进行尝试。已知编码该蛋白的基因在正链RNA病毒中是保守的。这使得能够重新利用针对早期报道的RdRP抑制剂设计的药物。一种这样的强抑制剂是已用于对抗埃博拉感染的remdesivir。采用经典分子动力学和系综对接方法研究了Remdesivir与SARS CoV-2 RdRP的结合。对载脂蛋白和Remdesivir结合形式的RdRP模拟的比较研究显示，在Remdesivir存在下，模板进入位点被阻断。通过主成分分析捕获导致该事件的构象变化。的构象和热力学参数支持的实验信息参与的关键精氨酸，丝氨酸和天冬氨酸残基属于RdRP功能的保守基序。观察到包含SER 759、ASP 760和ASP 761（SDD）的催化位点与瑞德西韦形成强接触。这些残基与Remdesivir的显著强的相互作用可以推断后者的结合类似于正常核苷酸，从而通过RdRP的核酸外切酶活性保持未鉴定。Remdesivir的集合对接也包括与抑制剂相互作用的类似残基的参与。通过计算机模拟方法，RdRP与Remdesivir的保守残基之间的关键相互作用的信息可能有助于设计抑制剂。Remdesivir结合RdRP的构象变化导致其抑制。
The efforts towards developing a potential drug against the current global pandemic, COVID-19, have increased in the past few months. Drug development strategies to target the RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are being tried worldwide. The gene encoding this protein, is known to be conserved amongst positive strand RNA viruses. This enables an avenue to repurpose the drugs designed against earlier reported inhibitors of RdRP. One such strong inhibitor is remdesivir which has been used against EBOLA infections. The binding of remdesivir to RdRP of SARS-CoV-2 has been studied using the classical molecular dynamics and ensemble docking approach. A comparative study of the simulations of RdRP in the apo and remdesivir-bound form revealed blocking of the template entry site in the presence of remdesivir. The conformation changes leading to this event were captured through principal component analysis. The conformational and thermodynamic parameters supported the experimental information available on the involvement of crucial arginine, serine and aspartate residues belonging to the conserved motifs in RdRP functioning. The catalytic site comprising of SER 759, ASP 760, and ASP 761 (SDD) was observed to form strong contacts with remdesivir. The significantly strong interactions of these residues with remdesivir may infer the latter's binding similar to the normal nucleotides thereby remaining unidentified by the exonuclease activity of RdRP. The ensemble docking of remdesivir too, comprehended the involvement of similar residues in interaction with the inhibitor. This information on crucial interactions between conserved residues of RdRP with remdesivir through in silico approaches may be useful in designing inhibitors. Conformational changes in the remdesivir-bound RdRP leading to its inhibition.
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DOI：
10.1016/j.ijantimicag.2020.105933
发表时间：
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