An in-silico pharmacophore-based molecular docking study to evaluate the inhibitory potentials of novel fungal triterpenoid Astrakurkurone analogues against a hypothetical mutated main protease of SARS-CoV-2 virus
COVID 19; MD Simulation; Phytochemicals; Principal component analysis; ZINC compounds
Background: The main protease is an important structural protein of SARS-CoV-2, essential for its survivability inside a human host. Considering current vaccines' limitations and the absence of approved therapeutic targets, Mpro may be regarded as the potential candidate drug target. Novel fungal phytocompound Astrakurkurone may be studied as the potential Mpro inhibitor, considering its medicinal properties reported elsewhere. Methods: In silico molecular docking was performed with Astrakurkurone and its twenty pharmacophore-based analogues against the native Mpro protein. A hypothetical Mpro was also constructed with seven mutations and targeted by Astrakurkurone and its analogues. Furthermore, multiple parameters such as statistical analysis (Principal Component Analysis), pharmacophore alignment, and drug likeness evaluation were performed to understand the mechanism of protein-ligand molecular interaction. Finally, molecular dynamic simulation was done for the top-ranking ligands to validate the result. Result: We identified twenty Astrakurkurone analogues through pharmacophore screening methodology. Among these twenty compounds, two analogues namely, ZINC89341287 and ZINC12128321 showed the highest inhibitory potentials against native and our hypothetical mutant Mpro, respectively (?7.7 and ?7.3 kcal mol?1) when compared with the control drug Telaprevir (?5.9 and ?6.0 kcal mol?1). Finally, we observed that functional groups of ligands namely two aromatic and one acceptor groups were responsible for the residual interaction with the target proteins. The molecular dynamic simulation further revealed that these compounds could make a stable complex with their respective protein targets in the near-native physiological condition. Conclusion: To conclude, Astrakurkurone analogues ZINC89341287 and ZINC12128321 can be potential therapeutic agents against the highly infectious SARS-CoV-2 virus. 2022 Elsevier Ltd
Nag A.; Dasgupta A.; Sengupta S.; Lai T.K.; Acharya K.
Computers in Biology and Medicine, Vol-152
All Open Access; Bronze Open Access; Green Open Access
ISSN: 104825; PubMed ID: 36565483; CODEN: CBMDA
https://doi.org/10.1016/j.compbiomed.2022.106433 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144556537&doi=10.1016%2fj.compbiomed.2022.106433&partnerID=40&md5=f0cb22523215711163b43da252e6540c
Nag A., Department of Life Sciences, CHRIST (Deemed to be University), Karnataka, Bangalore, India; Dasgupta A., Department of Botany, University of Calcutta, West Bengal, Kolkata, India; Sengupta S., Department of Life Sciences, CHRIST (Deemed to be University), Karnataka, Bangalore, India; Lai T.K., Department of Chemistry, Vidyasagar Metropolitan College, West Bengal, Kolkata, India; Acharya K., Department of Botany, University of Calcutta, West Bengal, Kolkata, India