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

Publication date: Dec 15, 2024

The global outbreak of COVID-19 infection is the first pandemic the world has experienced in this 21 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 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 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 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.

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Concepts Keywords
Coronavirus Drug repurposing
Global Field-based 3D-QSAR
Hydrophobic Molecular docking-based QSAR
Pandemic Pharmacophore mapping
Therapy SARS-CoV-2 3CLpro inhibitors
Structure-based molecular modelling

Semantics

Type Source Name
disease MESH COVID-19
disease MESH infection
disease MESH severe acute respiratory syndrome
disease IDO site
drug DRUGBANK Amino acids
drug DRUGBANK Elobixibat

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