Exploring the key structural attributes and chemico-biological interactions of pyridinone-based SARS-CoV-2 3CLpro inhibitors through validated structure-based drug design strategies

Suvankar Banerjee; Sandip Kumar Baidya; Balaram Ghosh; Tarun Jha; Nilanjan Adhikari

doi:10.1016/j.heliyon.2024.e40404

Exploring the key structural attributes and chemico-biological interactions of pyridinone-based SARS-CoV-2 3CL^pro inhibitors through validated structure-based drug design strategies

Heliyon. 2024 Nov 15;10(23):e40404. doi: 10.1016/j.heliyon.2024.e40404. eCollection 2024 Dec 15.

Authors

Suvankar Banerjee¹, Sandip Kumar Baidya¹, Balaram Ghosh², Tarun Jha¹, Nilanjan Adhikari¹

Affiliations

¹ Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
² Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.

Abstract

The global outbreak of COVID-19 infection is the first pandemic the world has experienced in this 21^st century. The novel coronavirus 2019 (nCoV-19) also called the SARS-CoV-2 is the reason behind the severe acute respiratory syndrome (SARS) that led to this worldwide crisis. In this current post-pandemic situation, despite having effective vaccines, the paucity of orally administrable drug molecules for such infections is a major drawback in this current scenario. Among the different viral enzymes, the SARS-CoV-2 3CL^pro is an encouraging target for effective drug discovery and development. In this context, the understanding of the requirements of the small molecules at the active site and their interactions is a crucial aspect of such drug candidate development. Here in this study, structure-based pharmacophore model development and molecular docking-dependent 2D-interaction-based and 3D-field-based QSAR studies have been carried out for a set of potential SARS-CoV-2 3CL^pro inhibitors. This study exposed the importance of interactions with amino acids of the active site (such as Leu167 and Gln189 amino acid residues) as well as the importance of hydrogen bond acceptor groups at the S2 and S1' pockets. The presence of hydrophobic aromatic features as well as hydrophobic contacts at the S1 and S4 pockets were also found to have a key contribution to the SARS-CoV-2 3CL^pro inhibition. Moreover, the screened drug candidate Elobixibat from the structure-based virtual screening also explored promising results as evidenced in MD simulation study and thus, can be a promising drug candidate that can be repurposed to assist in the development of effective anti-SARS-CoV-2 therapy.

Keywords: Drug repurposing; Field-based 3D-QSAR; Molecular docking-based QSAR; Pharmacophore mapping; SARS-CoV-2 3CLpro inhibitors; Structure-based molecular modelling.