Dual inhibition of inflammatory mediators and Coronaviridae main proteases by 2,5-disubstituted 1,3,4-oxadiazoles: a computational study

Given the critical role of pro-inflammatory proteins, cyclooxygenase-2 (COX-2) and Interleukin-1β (IL-1β), in viral infections and the high bioactivity of 1,3,4-oxadiazoles, this study investigates 2,5-disubstitutted 1,3,4-oxadiazoles via molecular docking against COX-2, IL-1β, and coronavirus main proteases to assess their dual anti-inflammatory and antiviral potential. Molecular docking and SAR analysis identified compounds 5 m and 5n as lead candidates with strong affinities for COX-2, IL-1β, and main proteases of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and hCoV. Key interactions include hydrophobic/electrostatic binding with catalytic residues, such as Arg120 in COX-2 and the His41-Cys145 dyad in viral proteases, suggesting a disruptive effect on enzymatic functions. SAR studies reveal that R₃ substitution (H > Me > Ph) enhances anti-inflammatory activity, while distinct aromatic rings contribute to selective inhibition of viral proteases. Molecular dynamics (MD) simulations confirmed the stability of ligand-protein interactions, with 5 m inducing the most conformational changes in inflammatory proteins and significant structural compression in viral proteases. Notably, compound 5 m induced structural compression in MERS-CoV and hCoV main proteases, potentially disrupting their enzymatic function. While nirmatrelvir caused the highest compression in SARS-CoV-2 M^pro, 5 m exhibited remarkable structural effects, further validating its antiviral potential. MM/PBSA and MD simulations highlight 5 m and 5n as promising anti-inflammatory and antiviral agents, with superior COX-2 and viral protease binding via electrostatic and van der Waals interactions. Overall, this study provides a strong foundation for developing 2,5-disubstituted 1,3,4-oxadiazoles as innovative, dual-function therapeutics. The promising activities of 5 m and 5n underscores their potential as next-generation drugs targeting inflammation and viral replication.