Dual Inhibition of DDR-2 and ADAMTS-5 by Novel 2-Substituted Quinazoline Derivatives: A Computational Approach for Disease-Modifying Osteoarthritis Drugs

Osteoarthritis (OA) is a degenerative joint disease marked by Articular cartilage breakdown, subchondral bone remodelling, and synovial inflammation. Current treatments focus primarily on symptom relief, highlighting the urgent need for disease-modifying osteoarthritis drugs (DMOADs). This study presents a dual-targeted therapeutic approach by inhibiting two critical enzymes involved in cartilage degradation: Discoidin Domain Receptor 2 (DDR2) and ADAMTS-5 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5). A virtual library of 175 quinazolinone-based ligands was developed using pharmacophore modelling. High-resolution protein structures (PDB IDs: 7AZB for DDR2 and 2RJQ for ADAMTS-5) were validated through Ramachandran plot analysis to ensure structural accuracy. Ligand structures underwent energy minimization, and their novelty was verified via the PubChem database. ADMET analysis confirmed favourable pharmacokinetic and toxicity profiles in accordance with Lipinski’s Rule of Five. Molecular docking studies revealed strong binding interactions for several ligands, with HMJ48, HMJ92, and HMJ155 demonstrating superior binding affinities compared to the standard drug Celecoxib. These findings suggest that quinazolinone derivatives hold significant promise as dual inhibitors for OA treatment. The results offer a foundation for future experimental studies aimed at developing effective, disease-modifying therapies.