Computational Drug Discovery and Toxicological Profiling of Novel Quinoline Derivatives: Insights from ADMET Analysis, Molecular Docking, and Dynamics Simulations for Antiviral Applications

Abstract

This study explores the antiviral potential of a novel series of quinoline derivatives using an integrated computational approach, with a particular focus on their inhibitory activity against the 2′-O-methyltransferase (MTase) enzyme of the yellow fever virus (YFV). The MTase enzyme, which plays a critical role in viral RNA capping and immune evasion, was selected as a strategic target (PDB ID: 3EVA). A logical approach was used to generate a structurally diverse library of quinoline analogs, followed by virtual screening of their pharmacokinetic properties and drug-likeness using the SwissADME and pkCSM platforms. Molecular docking analyses revealed that several compounds exhibited strong binding affinities to the MTase active site, interacting with conserved catalytic residues. The most promising candidates—Q11, Q12, and Q15—were further subjected to molecular dynamics (MD) simulations to validate the stability of the ligand–enzyme complexes. These compounds demonstrated stable binding behavior throughout the 100-nanosecond simulation period, as evidenced by root-mean-square deviation (RMSD) values remaining below 2 Å. Overall, the results suggest that the proposed quinoline derivatives possess favorable drug-like properties and exhibit strong potential for targeting the MTase enzyme of the yellow fever virus, making them promising scaffolds for the development of future antiviral agents.