Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310027, China.
Shanghai Institute for Advanced Study, Zhejiang University, Shanghai 201203, China.
Biomolecules. 2023 Feb 14;13(2):359. doi: 10.3390/biom13020359.
The emergence of the recent pandemic causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an alarming situation worldwide. It also prompted extensive research on drug repurposing to find a potential treatment for SARS-CoV-2 infection. An active metabolite of the hyperlipidemic drug fenofibrate (also called fenofibric acid or FA) was found to destabilize the receptor-binding domain (RBD) of the viral spike protein and therefore inhibit its binding to human angiotensin-converting enzyme 2 (hACE2) receptor. Despite being considered as a potential drug candidate for SARS-CoV-2, FA's inhibitory mechanism remains to be elucidated. We used molecular dynamics (MD) simulations to investigate the binding of FA to the RBD of the SARS-CoV-2 spike protein and revealed a potential cryptic FA binding site. Free energy calculations were performed for different FA-bound RBD complexes. The results suggest that the interaction of FA with the cryptic binding site of RBD alters the conformation of the binding loop of RBD and effectively reduces its binding affinity towards ACE2. Our study provides new insights for the design of SARS-CoV-2 inhibitors targeting cryptic sites on the RBD of SARS-CoV-2.
近期引发严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的大流行的出现，在全球范围内造成了令人震惊的局面。它还促使人们广泛研究药物再利用，以寻找治疗 SARS-CoV-2 感染的潜在方法。高脂血症药物非诺贝特（也称为非诺贝特酸或 FA）的一种活性代谢物被发现可以破坏病毒刺突蛋白的受体结合域（RBD），从而抑制其与人类血管紧张素转换酶 2（hACE2）受体的结合。尽管 FA 被认为是 SARS-CoV-2 的潜在候选药物，但 FA 的抑制机制仍有待阐明。我们使用分子动力学（MD）模拟研究了 FA 与 SARS-CoV-2 刺突蛋白的 RBD 的结合，并揭示了一个潜在的隐匿 FA 结合位点。我们对不同 FA 结合的 RBD 复合物进行了自由能计算。结果表明，FA 与 RBD 的隐匿结合位点的相互作用改变了 RBD 的结合环构象，并有效地降低了其与 ACE2 的结合亲和力。我们的研究为设计针对 SARS-CoV-2 RBD 隐匿位点的 SARS-CoV-2 抑制剂提供了新的见解。
