Effect of computationally designed fragment-based analogs on the RBD–ACE2 complex of the SARS-CoV-2 P.1 variant†

IF 3.2 3区 工程技术 Q2 CHEMISTRY, PHYSICAL
Surabhi Lata and Mohd. Akif
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Abstract

The binding of the receptor binding domain (RBD) of spike protein to the human ACE2 receptor is the primary step in the SARS-CoV-2 infection process. Spike protein has been an important therapeutic target. Emerging variants of SARS-CoV-2 have been imposing a significant challenge. Variants, especially with mutations on the RBD of spike protein, provide enhanced affinity towards the hACE2 receptor compared to the wild-type. Despite the development of many therapeutics, their efficacy towards the variants remains poor. In the present study, we used a fragment replacement approach to probe the fragment's space for analog design. We screened various fragments based on the geometric requirements to fit within the specified local environments of the RBD–ACE2 complex. Among all the screened analogs, two showed a better binding affinity with the RBD–ACE2 complex of the P.1 variant. Our all-atom simulations and free-energy calculations revealed a stable interaction of analogs with the interface residues of the RBD–ACE2 complex. The binding of analogs influenced the interactions of the key residues and led to structural interference in the complex. Essential dynamics analysis revealed that both analogs induce a change in the dynamic motion throughout the complex. The designed analogs may modulate the dynamics of the RBD–ACE2 complex formation and can be used as one of the lead molecules to interfere with the initial infection process of COVID-19 infections.

Abstract Image

基于计算设计的片段类似物对 SARS-CoV-2 P.1 变体的 RBD-ACE2 复合物的影响
尖峰蛋白的受体结合域(RBD)与人类 ACE2 受体的结合是 SARS-CoV-2 感染过程的首要步骤。尖峰蛋白一直是一个重要的治疗靶点。新出现的 SARS-CoV-2 变异体带来了巨大挑战。与野生型相比,变异株(尤其是尖峰蛋白 RBD 上的突变)对 hACE2 受体的亲和力更强。尽管开发了许多治疗药物,但它们对变异体的疗效仍然很差。在本研究中,我们采用了片段置换的方法来探测片段的空间。我们根据适合 RBD-ACE2 复合物特定局部环境的几何要求筛选了各种片段。在所有筛选出的类似物中,有两种与 P.1 变体的 RBD-ACE2 复合物有更好的结合亲和力。我们的全原子模拟和自由能计算显示,类似物与 RBD-ACE2 复合物的界面残基有稳定的相互作用。类似物的结合影响了关键残基的相互作用,并导致了复合物的结构干扰。基本动力学分析表明,两种类似物都会导致整个复合物的动态运动发生变化。所设计的类似物可能会调节 RBD-ACE2 复合物形成的动力学,可用作干扰 COVID-19 感染初期感染过程的先导分子之一。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Systems Design & Engineering
Molecular Systems Design & Engineering Engineering-Biomedical Engineering
CiteScore
6.40
自引率
2.80%
发文量
144
期刊介绍: Molecular Systems Design & Engineering provides a hub for cutting-edge research into how understanding of molecular properties, behaviour and interactions can be used to design and assemble better materials, systems, and processes to achieve specific functions. These may have applications of technological significance and help address global challenges.
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