Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CL^pro: A Study by Applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

Title:Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CL^pro: A Study by Applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

Volume: 19 Issue: 7

Author(s): Igor José dos Santos Nascimento*, Thiago Mendonça de Aquino and Edeildo Ferreira da Silva-Júnior*

Affiliation:

• Laboratory of Computational Chemistry and Modeling of Biomolecules, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió-AL, Brazil
• Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, Brazil

• Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Maceió, Brazil
• Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, Brazil

Keywords: SARS-CoV-2, structure-based drug discovery, virtual screening, molecular modeling, drug repurposing; molecular dynamics.

Abstract:

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential.

Methods: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds.

Results: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, R_g, SASA graphics. They also showed interactions with the catalytic dyad (His⁴¹ and Cys¹⁴⁵) and other essential residues for activity (Glu¹⁶⁶ and Gln¹⁸⁹) and high affinity for MM-PBSA, with possible covalent inhibition mechanism.

Conclusion: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

Cite this article as:

Santos Nascimento José dos Igor*, Aquino Mendonça de Thiago and Silva-Júnior Ferreira da Edeildo*, Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CL^pro: A Study by Applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking, Letters in Drug Design & Discovery 2022; 19 (7) . https://dx.doi.org/10.2174/1570180819666220106110133