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Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease.

ABSTRACT: To fight against the devastating coronavirus disease 2019 (COVID-19), identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is necessary. To contribute to this effort, we selected a human metabolites database containing waters and lipid-soluble metabolites to screen against the 3-chymotrypsin-like proteases (3CL^pro) protein of SARS-CoV-2. The top 8 hits from virtual screening displayed a docking score varying between ~ - 11 and ~ - 14 kcal/mol. Molecular dynamics simulations complement the virtual screening study in conjunction with the molecular mechanics generalized Born surface area (MM/GBSA) scheme. Our analyses revealed that (HMDB0132640) has the best glide docking score, - 14.06 kcal/mol, and MM-GBSA binding free energy, - 18.08 kcal/mol. The other three lead molecules are also selected along with the top molecule through a critical inspection of their pharmacokinetic properties. HMDB0132640 displayed a better binding affinity than the other three compounds (HMDB0127868, HMDB0134119, and HMDB0125821) due to increased favorable contributions from the intermolecular electrostatic and van der Waals interactions. Further, we have investigated the ligand-induced structural dynamics of the main protease. Overall, we have identified new compounds that can serve as potential leads for developing novel antiviral drugs against SARS-CoV-2 and elucidated molecular mechanisms of their binding to the main protease. Identification of probable hits from human metabolites against SARS-CoV-2 using integrated computational approaches-Missed against MS.

SUBMITTER: Roy R

PROVIDER: S-EPMC9385416 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease.

Roy Rajarshi R Sk Md Fulbabu MF Tanwar Omprakash O Kar Parimal P

Molecular diversity 20220818 4

To fight against the devastating coronavirus disease 2019 (COVID-19), identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is necessary. To contribute to this effort, we selected a human metabolites database containing waters and lipid-soluble metabolites to screen against the 3-chymotrypsin-like proteases (3CL<sup>pro</sup>) protein of SARS-CoV-2. The top 8 hits from virtual screening displayed a docking score varying between ~ - 11 and ~ - 14 kcal/mol. Molecular dynamic ...[more]

PMID: 35978064

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Project description:BackgroundThe sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19.ResultsMolecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood-brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1-T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target.ConclusionsHybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.

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Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease.

Publications

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease.

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