ABSTRACT
The COVID-19 pandemic caused by a novel coronavirus (SARS-CoV-2) is a serious health concern in the twenty-first century for scientists, health workers, and all humans. The absence of specific biotherapeutics requires new strategies to prevent the spread and prophylaxis of the novel virus and its variants. The SARS-CoV-2 virus shows pathogenesis by entering the host cells via spike protein and Angiotensin-Converting Enzyme 2 receptor protein. Thus, the present study aims to compute the binding energies between a wide range of bacteriocins with receptor-binding domain (RBD) on spike proteins of wild type (WT) and beta variant (lineage B.1.351). Molecular docking analyses were performed to evaluate binding energies. Upon achieving the best bio-peptides with the highest docking scores, further molecular dynamics (MD) simulations were performed to validate the structure and interaction stability. Protein-protein docking of the chosen 22 biopeptides with WT-RBD showed docking scores lower than -7.9 kcal/mol. Pediocin PA-1 and salivaricin P showed the lowest (best) docking scores of - 12 kcal/mol. Pediocin PA-1, salivaricin B, and salivaricin P showed a remarkable increase in the double mutant's predicted binding affinity with -13.8 kcal/mol, -13.0 kcal/mol, and -12.5 kcal/mol, respectively. Also, a better predicted binding affinity of pediocin PA-1 and salivaricin B against triple mutant was observed compared to the WT. Thus, pediocin PA-1 binds stronger to mutants of the RBD, particularly to double and triple mutants. Salivaricin B showed a better predicted binding affinity towards triple mutant compared to WT, showing that it might be another bacteriocin with potential activity against the SARS-CoV-2 beta variant. Overall, pediocin PA-1, salivaricin P, and salivaricin B are the most promising candidates for inhibiting SARS-CoV-2 (including lineage B.1.351) entrance into the human cells. These bacteriocins derived from lactic acid bacteria hold promising potential for paving an alternative way for treatment and prophylaxis of WT and beta variants.
ABSTRACT
The changes in the SARS-CoV-2 genome have resulted in the emergence of new variants. Some of the variants have been classified as variants of concern (VOC). These strains have higher transmission rate and improved fitness. One of the prevalent were the Omicron variant. Unlike previous VOCs, the Omicron possesses fifteen mutations on the spike protein's receptor binding domain (RBD). The modifications of spike protein's key amino acid residues facilitate the virus' binding capability against ACE2, resulting in an increase in the infectiousness of Omicron variant. Consequently, investigating the prevention and treatment of the Omicron variant is crucial. In the present study, we aim to explore the binding capacity of twenty-two bacteriocins derived from Lactic Acid Bacteria (LAB) against the Omicron variant by using protein-peptidedocking and molecular dynamics (MD) simulations. The Omicron variant RBD was prepared by introducing fifteen mutations using PyMol. The protein-peptide complexes were obtained using HADDOCK v2.4 docking webserver. Top scoring complexes obtained from HADDOCK webserver were retrieved and submitted to the PRODIGY server for the prediction of binding energies. RBD-bacteriocin complexes were subjected to MD simulations. We discovered promising peptide-based therapeutic candidates for the inhibition of Omicron variant for example Salivaricin B, Pediocin PA 1, Plantaricin W, Lactococcin mmfii and Enterocin A. The lead bacteriocins, except Enterocin A, are biosynthesized by food-grade lactic acid bacteria. Our study puts forth a preliminary information regarding potential utilization of food-grade LAB-derived bacteriocins, particularly Salivaricin B and Pediocin PA 1, for Covid-19 treatment and prophylaxis.Communicated by Ramaswamy H. Sarma.
ABSTRACT
The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.