The Inhibitory Potential of Ferulic Acid Derivatives against the SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics, and ADMET Evaluation

Abstract

The main protease (Mpro) of SARS-CoV-2 is an appealing target for the development of antiviral compounds, due to its critical role in the viral life cycle and its high conservation among different coronaviruses and the continuously emerging mutants of SARS-CoV-2. Ferulic acid (FA) is a phytochemical with several health benefits that is abundant in plant biomass and has been used as a basis for the enzymatic or chemical synthesis of derivatives with improved properties, including antiviral activity against a range of viruses. This study tested 54 reported FA derivatives for their inhibitory potential against Mpro by in silico simulations. Molecular docking was performed using Autodock Vina, resulting in comparable or better binding affinities for 14 compounds compared to the known inhibitors N3 and GC376. ADMET analysis showed limited bioavailability but significantly improved the solubility for the enzymatically synthesized hits while better bioavailability and druglikeness properties but higher toxicity were observed for the chemically synthesized ones. MD simulations confirmed the stability of the complexes of the most promising compounds with Mpro, highlighting FA rutinoside and compound e27 as the best candidates from each derivative category.

Ferulic Acid: A Review of Pharmacology, Toxicology, and Therapeutic Effects on Pulmonary Diseases

“…The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused the outbreak of coronavirus disease 2019, against which the therapeutic target is the SARS-CoV-2 main protease [200]. Some FA derivatives, such as FA rutinoside and raffinose ferulate, show comparable or better binding affinities for the main protease of SARS-CoV-2 as confirmed inhibitors, and might have antiviral potential against coronavirus disease 2019 [201].…”

Neuroprotective potentials of ferulic acid against intracerebral hemorrhage COVID-19 through using network pharmacology approach and molecular docking analysis

“…Preliminary investigations have suggested a putative role for ferulic acid in mitigating the impact of the viral infection, although comprehensive studies are still warranted to establish its therapeutic efficacy definitively. A comprehensive analysis using molecular docking, molecular dynamics indicates inhibitory potential of ferulic acid derivatives against the main protease (M pro ) of SARS-CoV-2 ( Antonopoulou et al, 2022 ). Some of ferulic acid derivatives have been found with promising anti-viral activity against SARS-CoV2, characterized with the inhibition of viral replication of SARS-CoV2 by 82% ( Pasquereau et al, 2022 ).…”

Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

“…Diels 464 . The components of Angelicae Sinensis Radix have potential inhibitory effects on SARS-CoV-2 Mpro 465 . The major components of Angelicae Sinensis Radix include Angelica polysaccharides, organic acids, phthalides, and flavonoids, of which ferulic acid is the most important active component 466 .…”