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Novel hybrid antiviral VTRRT-13V2.1 against SARS-CoV2 main protease: retro-combinatorial synthesis and molecular dynamics analysis.

ABSTRACT: The COVID-19 pandemic caused by SARS-CoV-2 has now emerged as a global health problem and is responsible for high mortality and morbidity. The SARS-CoV-2 main protease (M^pro) emerged as a promising drug target because of its essential role in the processing of polyproteins, which is translated from viral RNA. The present study reports a designed novel hybrid antiviral molecule (VTRRT-13.V2.1) against SARS-CoV2 main protease. A series of different combinations of hybrid antiviral were generated from nonspecific antiviral molecules currently used to control COVID-19. To enhance the specificity of the designed hybrid antiviral molecule, the core pocket region of the active site of M^pro protein was targeted. In-silico screening, molecular mechanics, molecular dynamics simulation (MDS) analysis identified a hybrid VTRRT-13.V2 molecule. Retrosynthetic analysis and combinatorial synthesis generated 1000 analogs of VTRRT-13.V2 molecules. Docking, molecular mechanics, and MDS analysis selected VTRRT-13.V2.1 as a possible inhibitor for SARS-CoV2 main protease. Comparative analysis of all the results showed that VTRRT-13.V2.1 have the highest docking Glide score (-12.28 kcal/mol) and best binding energy (-52.23 kcal/mol) as compared to the other hybrid constructs such as VTRRT-13.V2 (-9.47 and -47.36 kcal/mol), VTRRT-13 (-8.9 and -47.55 kcal/mol), and current antiviral investigated. The mutational sensitivity screening showed that binding residues of M^pro are not present in mutation hotspots. It was also observed that VTRRT-13.V2.1 does not have any human off-targets. SARS-CoV2 main protease is essential for the survival of this virus; hence, a designed novel hybrid antiviral molecule (VTRRT-13.V2.1) might be useful to control the infection of COVID-19 infection.

SUBMITTER: Tiwari V

PROVIDER: S-EPMC7526676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The recent coronavirus outbreak has changed the world's economy and health sectors due to the high mortality and transmission rates. Because the development of new effective vaccines or treatments against the virus can take time, an urgent need exists for the rapid development and design of new drug candidates to combat this pathogen. Here, we obtained antiviral peptides obtained from the data repository of antimicrobial peptides (DRAMP) and screened their predicted tertiary structures for the ability to inhibit the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using multiple combinatorial docking programs, including PatchDock, FireDock, and ClusPro. The four best peptides, DRAMP00877, DRAMP02333, DRAMP02669, and DRAMP03804, had binding energies of -1125.3, -1084.5, -1005.2, and -924.2 Kcal/mol, respectively, as determined using ClusPro, and binding energies of -55.37, -50.96, -49.25, -54.81 Kcal/mol, respectively, as determined using FireDock, which were better binding energy values than observed for other peptide molecules. These peptides were found to bind with the active cavity of the SARS-CoV-2 main protease; at Glu166, Cys145, Asn142, Phe140, and Met165, in addition to the substrate-binding sites, Domain 2 and Domain 3, whereas fewer interactions were observed with Domain 1. The docking studies were further confirmed by a molecular dynamics simulation study, in which several descriptors, including the root-mean-square difference (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), and hydrogen bond formation, confirmed the stable nature of the peptide-main protease complexes. Toxicity and allergenicity studies confirmed the non-allergenic nature of the peptides. This present study suggests that these identified antiviral peptide molecules might inhibit the main protease of SARS-CoV-2, although further wet-lab experiments remain necessary to verify these findings.

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Novel hybrid antiviral VTRRT-13V2.1 against SARS-CoV2 main protease: retro-combinatorial synthesis and molecular dynamics analysis.

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