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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.
Sekar, P Chandra; Srinivasan, E; Chandrasekhar, G; Paul, D Meshach; Sanjay, G; Surya, S; Kumar, N S Arun Raj; Rajasekaran, R.
  • Sekar PC; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Srinivasan E; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Chandrasekhar G; Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (Deemed to Be University), Chennai, Tamil Nadu, India.
  • Paul DM; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Sanjay G; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Surya S; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Kumar NSAR; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
  • Rajasekaran R; Quantitative Biology Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to Be University), Vellore, Tamil Nadu, India.
J Mol Model ; 28(5): 128, 2022 Apr 24.
Article in English | MEDLINE | ID: covidwho-1802772
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antimicrobial Cationic Peptides / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 / COVID-19 Drug Treatment Limits: Animals / Humans Language: English Journal: J Mol Model Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00894-022-05117-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antimicrobial Cationic Peptides / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / COVID-19 / COVID-19 Drug Treatment Limits: Animals / Humans Language: English Journal: J Mol Model Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00894-022-05117-8