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The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies.

ABSTRACT: An investigation has been carried out on natural products from dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CL^pro) using an in silico approach. Inhibition of the 3CL^pro enzyme is a promising target in stopping the replication of the SARS-CoV-2 virus through inhibition of the subsite binding pocket. The redocking process aims to determine the 3CL^pro active sites. The redocking requirement showed a good pose with an RMSD value of 1.39 Å. The combination of molecular docking and MD simulation shows the results of DD13 as a candidate which had a good binding affinity (kcal mol^-1) to inhibit the 3CL^pro enzyme activity. Prediction of binding free energy (kcal mol^-1) of DD13 using the Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GBSA) approach shows the results ΔG _{bind(MM-GBSA)}: -52.33 ± 0.34 and ΔG _{bind(MM-PBSA)}: -43.52 ± 0.42. The key residues responsible for the inhibition mechanism are Hie41, Ser46, Met49, Asn142, Cys145, Hie163, Met165, and Gln189. Additionally, pharmacokinetic prediction recommended that DD13 had promising criteria as a drug candidate. The results demonstrated in this study provide theoretical information to obtain a potential inhibitor against the SARS-CoV-2 main protease.

SUBMITTER: Aminah NS

PROVIDER: S-EPMC9044469 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

Project description:COVID-19 disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has struck the whole world and raised severe health, economic, and social problems. Many scientists struggled to find a vaccine or an antiviral drug. Eventually, both vaccines and recommended drugs, repurposed drugs, or drug combinations were found, but new strains of SARS-CoV-2 continue to threaten human life and health. As part of the fight against COVID-19 disease, this study involves an in silico molecular docking analysis on the main protease (Mpro) of SARS-CoV-2. To this aim, a Schiff base compound was synthesized and characterized using spectroscopic techniques, including X-ray, FTIR, and UV-Vis. Surface analysis and electronic properties of this molecule were investigated using the DFT method. The drug-likeness parameters of the title compound were studied according to the rules of Lipinski, Veber, Ghose, Egan, and Muegge and were found in agreement with these rules. In silico toxicity analyses revealed that the new compound is a potentially mutagenic and carcinogenic chemical. The title compound was predicted to be an inhibitor of cytochrome P450 enzymes (5 CYPs). This inhibitory effect indicates a weak metabolism of the molecule in the liver. In addition, this compound was displayed good intestinal absorption and blood-brain barrier penetration. The druggability properties of the title compound were investigated, and SwissTargetPrediction predicted it to be a protease inhibitor. In this context, the SARS-CoV-2 main protease was selected as a biological target in molecular docking studies. Docking results were compared with the known native ligand N3 inhibitor. The value of binding energy between the Schiff base compound and the binding pocket of the main protease is higher than that of the reference ligand N3. The calculated free energies of binding of the Schiff base compound and the reference ligand N3 are -8.10 and -7.11 kcal/mol, respectively.

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The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies.

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