1st International and 10th National Iranian Conference on Bioinformatics

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Computational design of peptide inhibitors targeting the interaction of ACE2 and the spike receptor-binding domain of the SARS-CoV-2 Omicron variant

Paper ID : 1401-ICB10

Authors:

Fatemeh Arabi Jeshvaghani *

دانشگاه اصفهان

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh human coronavirus that causes the coronavirus disease (COVID-19) after attacking the upper respiratory system and may lead to respiratory, enteric, hepatic, and neurologic diseases. Omicron variant (B.1.1.529) is a recent SARS-CoV-2 variant of concern (VOC) with a large number of mutations in spike protein and with impacts on viral transmissibility, disease severity, and efficacy of vaccines and therapeutics [1]. Here, we designed a set of peptide inhibitors to block the protein–protein interactions (PPIs) of the receptor binding domain (RBD) of the SARS-CoV-2 Omicron variant with human ACE2 using computational methods. Based on the key interacting residues involved in the interaction site of RBD and ACE2 that were analyzed by hotspot prediction tools, PIC [2] and Ligplot+ [3], a set of inhibitory peptides was designed. CABS-dock [4] was used for molecular docking of designed peptides with spike protein of Omicron variant. Prodigy [5] and HawkDock [6] webservers predicted the binding affinity of peptide-protein complexes and MM/GBSA free energy decompositions. Drug-likeness and ADME-Tox analysis were done by SwissADME [7] and FAF-drugs4 [8] to compute the physicochemical descriptors and properties of the designed peptides. Peptides are less immunogenic than recombinant proteins or monoclonal antibodies, with higher solubility and better biological efficiency than therapeutic proteins. Antibodies cannot penetrate to the cell membrane to target intracellular PPIs and small molecules are not promising candidates for targeting challenging desired large and flat PPIs binding sites [9]. The designed interfering peptides with the most negative binding energies, the proper binding sites, and the acceptable properties are the potential candidates to develop as novel anticoronaviral therapeutics for COVID-19 or future related CoV’s outbreaks.

Keywords:

SARS-CoV-2; Protein-protein interactions; Inhibitory peptide; Omicron variant; Receptor-binding domain

Status : Paper Accepted (Poster Presentation)