COVID-19大流行是由于新型冠状病毒的传播而宣布的,SARS-CoV-2.病毒感染是由SARS-CoV-2受体结合域(RBD)和人ACE2受体(hACE2)之间的相互作用引起的。以前的计算研究已经确定了靶向RBD的重新利用的小分子,但很少有人在RBD-hACE2界面筛选药物。当研究仅关注药物与RBD之间的结合亲和力时,他们忽略了hACE2的影响,导致分析不完整。我们筛选了ACE抑制剂,并先前鉴定了与RBD-hACE2界面结合的SARS-CoV-2抑制剂,然后对福辛普利进行了500ns的无限制分子动力学(MD)模拟,fosinoprilat,赖诺普利,大黄素,Diquafosol,和physcion结合到界面以评估这些配体的结合特性。基于MM-GBSA分析,所有六个配体在界面中有利地结合并抑制RBD-hACE2相互作用。然而,当我们通过在与hACE2相互作用之前首先将药物与RBD结合来重复我们的模拟时,我们发现福辛普利,fosinoprilat,和赖诺普利导致强烈相互作用的三聚体复合物(RBD-药物-hACE2)。氢键和成对分解分析进一步表明福辛普利是最好的RBD抑制剂。然而,当赖诺普利受约束时,它稳定了三聚体复合物,因此,不是理想的潜在候选药物。总的来说,这些结果揭示了对RBD与hACE2结合至关重要的重要原子相互作用,并强调了在潜在候选药物的评估中包括所有蛋白质伴侣的重要性.
The COVID-19 pandemic was declared due to the spread of the novel coronavirus, SARS-CoV-2. Viral infection is caused by the interaction between the SARS-CoV-2 receptor binding domain (RBD) and the human ACE2 receptor (hACE2). Previous computational studies have identified repurposed small molecules that target the RBD, but very few have screened drugs in the RBD-hACE2 interface. When studies focus solely on the binding affinity between the drug and the RBD, they ignore the effect of hACE2, resulting in an incomplete analysis. We screened ACE inhibitors and previously identified SARS-CoV-2 inhibitors for binding to the RBD-hACE2 interface, and then conducted 500 ns of unrestrained molecular dynamics (MD) simulations of fosinopril, fosinoprilat, lisinopril, emodin, diquafosol, and physcion bound to the interface to assess the binding characteristics of these ligands. Based on MM-GBSA analysis, all six ligands bind favorably in the interface and inhibit the RBD-hACE2 interaction. However, when we repeat our simulation by first binding the drug to the RBD before interacting with hACE2, we find that fosinopril, fosinoprilat, and lisinopril result in a strongly interacting trimeric complex (RBD-drug-hACE2). Hydrogen bonding and pairwise decomposition analyses further suggest that fosinopril is the best RBD inhibitor. However, when lisinopril is bound, it stabilizes the trimeric complex and, therefore, is not an ideal potential drug candidate. Overall, these results reveal important atomistic interactions critical to the binding of the RBD to hACE2 and highlight the significance of including all protein partners in the evaluation of a potential drug candidate.