Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease,Molecular Systems Design & Engineering

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Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease
Molecular Systems Design & Engineering ( IF 3.2 ) Pub Date : 2021-11-18 , DOI: 10.1039/d1me00124h
Shunzhou Wan ₁ , Agastya P Bhati ₁ , Alexander D Wade ₁ , Dario Alfè _{2,

3} , Peter V Coveney _{1,

4}

Affiliation

Although researchers have been working tirelessly since the COVID-19 outbreak, so far only three drugs – remdesivir, ronapreve and molnupiravir – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput X-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CL^pro). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CL^pro. The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug–protein binding, in turn shedding light on the design and discovery of potential drugs.

中文翻译：

重新利用与 SARS-CoV-2 主要蛋白酶结合的药物的热力学和结构见解

尽管自 COVID-19 爆发以来研究人员一直在不知疲倦地工作，但迄今为止，只有三种药物——remdesivir、ronapreve 和 molnupiravir——已被批准在一些直接针对 SARS-CoV-2 病毒的国家使用。考虑到新药发现和开发的缓慢步伐和巨大成本，以及事情的紧迫性，将现有药物重新用于当前疾病是一个有吸引力的提议。在最近的一项研究中，对一些已获批准或正在进行临床试验的药物进行了高通量 X 射线晶体学筛查。已从药物库中鉴定出 37 种化合物，所有这些化合物均与 SARS-CoV-2 主要蛋白酶（3CL ^pro）。在目前的研究中，我们使用分子动力学模拟和基于集合的自由能方法，即使用连续溶剂近似 (ESMACS) 的分子动力学增强采样来研究上述化合物的一个子集。这里研究的药物高度多样化，与 3CL ^pro的不同结合位点和/或亚位点相互作用。将预测的自由能与可用的实验结果进行比较，发现它们非常一致。我们的研究还为相关药物-蛋白质结合的性质提供了详细的能量见解，从而为潜在药物的设计和发现提供了启示。

更新日期：2021-11-24

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