Initial phase of COVID-19 infection is associated with the binding of viral spike protein S1 receptor binding domain (RBD) with the host cell surface receptor, ACE2. Peptide inhibitors typically interact with spike proteins in order to block its interaction with ACE2, and this knowledge would promote the use of such peptides as therapeutic scaffolds. The present study examined the competitive inhibitor activity of a broad spectrum antimicrobial peptide, Dermaseptin-S4 (S4) and its analogues. Three structural S4 analogues viz., S4 (K₄), S4 (K₂₀) and S4 (K₄K₂₀) were modelled by substituting charged lysine for non-polar residues in S4 and subsequently, docked with S1. Further, the comparative analysis of inter-residue contacts and non-covalent intermolecular interactions among S1–S4 (K₄), S1–S4 (K₄K₂₀) and S1–ACE2 complexes were carried out to explore their mode of binding with S1. Interestingly, S1–S4 (K₄) established more inter-molecular interactions compared to S4 (K₄K₂₀) and S1–ACE2. In order to substantiate this study, the normal mode analysis (NMA) was conducted to show how the structural stability of the flexible loop region in S1 is affected by atomic displacements in unbound S1 and docked complexes. Markedly, the strong interactions consistently maintained by S1–S4 (K₄) complex revealed their conformational transition over the harmonic motion period. Moreover, S1–S4 (K₄) peptide complex showed a higher energy deformation profile compared to S1–S4 (K₄K₂₀), where the higher energy deformation suggests the rigidity of the docked complex and thus it’s harder deformability, which is also substantiated by molecular dynamics simulation. In conclusion, S1–S4 (K₄) complex has definitely exhibited a functionally significant dynamics compared to S1–ACE2 complex; this peptide inhibitor, S4 (K₄) will need to be considered as the best therapeutic scaffold to block SARS-CoV-2 infection.

COVID-19 感染的初始阶段与病毒刺突蛋白 S1 受体结合域 (RBD) 与宿主细胞表面受体 ACE2 的结合有关。肽抑制剂通常与刺突蛋白相互作用以阻止其与 ACE2 的相互作用，而这一知识将促进将此类肽用作治疗支架。本研究检查了广谱抗菌肽 Dermaseptin-S4 (S4) 及其类似物的竞争性抑制剂活性。三种结构 S4 类似物，即 S4 (K ₄ )、S4 (K ₂₀ ) 和 S4 (K ₄ K ₂₀) 通过用带电赖氨酸代替 S4 中的非极性残基进行建模，随后与 S1 对接。_{此外，对 S1-S4 (K 4} )、S1-S4 (K ₄ K ₂₀ ) 和 S1-ACE2 复合物之间的残基间接触和非共价分子间相互作用进行了比较分析，以探索它们与 S1 结合的方式. 有趣的是，与 S4 (K ₄ K _{20 ) 相比，S1-S4 (K 4} ) 建立了更多的分子间相互作用) 和 S1-ACE2。为了证实这项研究，进行了正常模式分析 (NMA)，以显示 S1 中柔性环区域的结构稳定性如何受到未结合 S1 和对接配合物中的原子位移的影响。值得注意的是，S1-S4 (K ₄ ) 复合物始终保持的强相互作用揭示了它们在谐波运动期间的构象转变。此外，与 S1-S4 (K ₄ K _{20 ) 相比，S1-S4 (K 4} ) 肽复合物表现出更高的能量变形曲线，其中更高的能量变形表明对接复合物的刚性，因此它更难变形，这也是通过分子动力学模拟证实。总之，S1-S4 (K ₄) 与 S1-ACE2 复合物相比，复合物肯定表现出功能上显着的动态；这种肽抑制剂 S4 (K ₄ ) 需要被视为阻断 SARS-CoV-2 感染的最佳治疗支架。