Potential targets of severe acute respiratory syndrome coronavirus 2 of clinical drug fluvoxamine: Docking and molecular dynamics studies to elucidate viral action. (7th December 2022)

• Record Type: Journal Article
• Authors: Panda, Saroj Kumar; Gupta, Parth Sarthi Sen; Rana, Malay Kumar
• Is Part Of: Cell biochemistry and function. Volume 41:Number 1(2023)
• Page Start: 98
• Page End: 111
• Publication Date: 2022-12-07
• Subjects: COVID‐19 -- fluvoxamine -- MMPBSA -- molecular docking -- molecular dynamics; Cytochemistry -- Periodicals; Cell metabolism -- Periodicals; Biochemistry -- Periodicals; Cytology -- Periodicals; 572
• DOI: 10.1002/cbf.3766
• Languages: English
• ISSNs: 0263-6484

Abstract

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration‐approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID‐19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID‐19 is still unknown. Fluvoxamine was docked with 11 SARS‐CoV‐2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain‐like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7‐MTase ((N7‐guanine)‐methyltransferase)–fluvoxamine, Mpro–fluvoxamine, and PLpro–fluvoxamine complexes are stable, with the lowest binding free energies of −105.1, −82.7, and − 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS‐CoV‐2. Significance statement: Although the antidepressant drug fluvoxamine was found to be clinically effective on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), there is a lack of molecular insights. The present study concerns fluvoxamine inhibiting, which molecular target (s) of SARS‐CoV‐2. It elucidated the mechanistic binding of the drug with 11 different SARS‐CoV‐2 targets. The top three targets that showed lower docking energies with fluvoxamine are nonstructural protein 14 (NSP14), papain‐like protease, and main protease (Mpro). Conformational stability and free energy analyses identified NSP14 (−105.1 kJ/mol) and Mpro (−82.7 kJ/mol) as the potential targets of fluvoxamine, revealing its multitarget nature. The hotspot residues identified in both targets, such as Glu166, Asp187, His41, and Cys145 in Mpro and Glu302, Gly333, and Phe426 in NSP14, could be useful to develop better drugs in the future. There are hotspot residues identified in both targets, such as Glu166, Asp187, His41, and Cys145 in Mpro and Glu302, Gly333, and Phe426 in NSP14, that could help develop better drugs in the future.