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Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

ABSTRACT: Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (M^pro) and papain-like protease (PL^pro) of SARS-CoV-2 using in silico methods to find out possible new drug candidate(s). Out of 63 compounds, epoxomicin showed the best binding affinity against the M^pro with CDocker energy of - 57.511 kcal/mol without any toxic effect. This compound was further taken for molecular dynamic simulation study, where the M^pro-epoxomicin complex was found to be stable with binding free energy - 79.315 kcal/mol. The possible inhibitory potential of the selected compound was determined by 3D-QSAR analysis and found to be 0.4447 µM against SARS-CoV-2 M^pro. Finally, the structure activity relationship of the compound was analyzed and two fragments responsible for overall good binding affinity of the compound at the active site of M^pro were identified. This study suggests a safe antimalarial drug, namely epoxomicin, as a probable inhibitor of SARS-CoV-2 M^pro which needs further validation by in vitro/in vivo studies before clinical use.

Supplementary information

The online version contains supplementary material available at 10.1007/s11224-022-01916-0.

SUBMITTER: Gogoi N

PROVIDER: S-EPMC9136827 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

Gogoi Neelutpal N Chowdhury Purvita P Goswami Ashis Kumar AK Das Aparoop A Chetia Dipak D Gogoi Bhaskarjyoti B

Structural chemistry 20220527 5

Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (M<sup>pro</sup>) and papain-like protease (PL<sup>pro</sup>) of SARS-CoV-2 u ...[more]

PMID: 35669793

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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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Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

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Publications

Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

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