Probing the competitive inhibitor efficacy of frog-skin alpha helical AMPs identified against ACE2 binding to SARS-CoV-2 S1 spike protein as therapeutic scaffold to prevent COVID-19.

In COVID-19 infection, the SARS-CoV-2 spike protein S1 interacts to the ACE2 receptor of human host, instigating the viral infection. To examine the competitive inhibitor efficacy of broad spectrum alpha helical AMPs extracted from frog skin, a comparative study of intermolecular interactions between viral S1 and AMPs was performed relative to S1-ACE2p interactions. The ACE2 binding region with S1 was extracted as ACE2p from the complex for ease of computation. Surprisingly, the Spike-Dermaseptin-S9 complex had more intermolecular interactions than the other peptide complexes and importantly, the S1-ACE2p complex. We observed how atomic displacements in docked complexes impacted structural integrity of a receptor-binding domain in S1 through conformational sampling analysis. Notably, this geometry-based sampling approach confers the robust interactions that endure in S1-Dermaseptin-S9 complex, demonstrating its conformational transition. Additionally, QM calculations revealed that the global hardness to resist chemical perturbations was found more in Dermaseptin-S9 compared to ACE2p. Moreover, the conventional MD through PCA and the torsional angle analyses indicated that Dermaseptin-S9 altered the conformations of S1 considerably. Our analysis further revealed the high structural stability of S1-Dermaseptin-S9 complex and particularly, the trajectory analysis of the secondary structural elements established the alpha helical conformations to be retained in S1-Dermaseptin-S9 complex, as substantiated by SMD results. In conclusion, the functional dynamics proved to be significant for viral Spike S1 and Dermaseptin-S9 peptide when compared to ACE2p complex. Hence, Dermaseptin-S9 peptide inhibitor could be a strong candidate for therapeutic scaffold to prevent infection of SARS-CoV-2.

Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation.

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.