Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus’s life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds’ binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of −49.37 ± 0.15 kcal/mol, followed by compound 7 (−39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (−23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug’s ability to bind better at the active site of the SARS-CoV-2 Mpro.

Unravelling Insights into the Evolution and Management of SARS-CoV-2

“…In addition, therapeutic options have been sought in natural products (terpenoids, alkaloids, saponins, and phenolics) with promising in vitro and in silico results for use in COVID-19 disease [158][159][160]. Among these, the most studied are resveratrol, quercetin, hesperidin, curcumin, myricetin, and betulinic acid, which were proposed as SARS-CoV-2 inhibitors [159].…”

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

“…Those approaches enable researchers to anticipate possible drug candidates' binding affinity, pharmacokinetics, and toxicity, offering vital insights into their potential efficacy and safety [7,46]. These approaches enable us to swiftly screen a large number of compounds, optimize therapeutic candidates, and minimize the time and cost associated with traditional drug development procedures [15,47].…”

“…Employing molecular docking, molecular dynamics (MD) simulations, and subsequent post-MD analyses, including hydrogen occupancy, we assessed the binding free energy profiles of the selected inhibitors against SARS-CoV-2. We also identified the specific amino acid residues responsible for the drug-binding interactions with SARS-CoV-2 Mpro [15]. Furthermore, another ongoing project, "In Silico Analysis of Repurposed Antiviral Drugs as Prospective Therapeutics for COVID-19: Molecular Docking and Dynamics Simulations Targeting the 3-Chymotrypsin-Like Protease (3CLPro)", focuses on Ritonavir, Lopinavir, Ombitasvir, and Paritaprevir as potential inhibitors of the 3CLPro enzyme, due to its critical role in viral replication.…”

A Comprehensive Analysis of Structural and Functional Changes Induced by SARS-CoV-2 Spike Protein Mutations

“…In a recent research article by our group entitled "Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation", we investigated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against the SARS-CoV-2 main protease [6]. In this study, we applied molecular docking, molecular dynamics (MD) simulations, percentage hydrogen occupancy, and other post-MD analyses to explain the selected compounds' binding free energy potential against SARS-CoV-2 and further identified the residues responsible for the drug-binding properties of the selected inhibitors against SARS-CoV-2 Mpro [6]. We also have an ongoing novel study entitled "In silico analysis of repurposed antiviral drugs as potential therapeutic agents for COVID-19: Molecular docking and dynamics simulations targeting the 3-chymotrypsin-like protease (3CLPro)".…”