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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 promot...

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Autores principales: Sekar, P. Chandra, Rajasekaran, R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811342/
https://www.ncbi.nlm.nih.gov/pubmed/33488318
http://dx.doi.org/10.1007/s10989-020-10149-w
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author Sekar, P. Chandra
Rajasekaran, R.
author_facet Sekar, P. Chandra
Rajasekaran, R.
author_sort Sekar, P. Chandra
collection PubMed
description 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 (K(4)), S4 (K(20)) and S4 (K(4)K(20)) 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 (K(4)), S1–S4 (K(4)K(20)) and S1–ACE2 complexes were carried out to explore their mode of binding with S1. Interestingly, S1–S4 (K(4)) established more inter-molecular interactions compared to S4 (K(4)K(20)) 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 (K(4)) complex revealed their conformational transition over the harmonic motion period. Moreover, S1–S4 (K(4)) peptide complex showed a higher energy deformation profile compared to S1–S4 (K(4)K(20)), 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 (K(4)) complex has definitely exhibited a functionally significant dynamics compared to S1–ACE2 complex; this peptide inhibitor, S4 (K(4)) will need to be considered as the best therapeutic scaffold to block SARS-CoV-2 infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10989-020-10149-w) contains supplementary material, which is available to authorized users.
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spelling pubmed-78113422021-01-18 Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation Sekar, P. Chandra Rajasekaran, R. Int J Pept Res Ther Article 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 (K(4)), S4 (K(20)) and S4 (K(4)K(20)) 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 (K(4)), S1–S4 (K(4)K(20)) and S1–ACE2 complexes were carried out to explore their mode of binding with S1. Interestingly, S1–S4 (K(4)) established more inter-molecular interactions compared to S4 (K(4)K(20)) 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 (K(4)) complex revealed their conformational transition over the harmonic motion period. Moreover, S1–S4 (K(4)) peptide complex showed a higher energy deformation profile compared to S1–S4 (K(4)K(20)), 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 (K(4)) complex has definitely exhibited a functionally significant dynamics compared to S1–ACE2 complex; this peptide inhibitor, S4 (K(4)) will need to be considered as the best therapeutic scaffold to block SARS-CoV-2 infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10989-020-10149-w) contains supplementary material, which is available to authorized users. Springer Netherlands 2021-01-16 2021 /pmc/articles/PMC7811342/ /pubmed/33488318 http://dx.doi.org/10.1007/s10989-020-10149-w Text en © The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature 2021 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Article
Sekar, P. Chandra
Rajasekaran, R.
Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title_full Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title_fullStr Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title_full_unstemmed Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title_short Could Dermaseptin Analogue be a Competitive Inhibitor for ACE2 Towards Binding with Viral Spike Protein Causing COVID19?: Computational Investigation
title_sort could dermaseptin analogue be a competitive inhibitor for ace2 towards binding with viral spike protein causing covid19?: computational investigation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811342/
https://www.ncbi.nlm.nih.gov/pubmed/33488318
http://dx.doi.org/10.1007/s10989-020-10149-w
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