Computational 3D Modeling-Based Identification of Inhibitors Targeting Cysteine Covalent Bond Catalysts for JAK3 and CYP3A4 Enzymes in the Treatment of Rheumatoid Arthritis

Abstract

This work aimed to find new inhibitors of the CYP3A4 and JAK3 enzymes, which are significant players in autoimmune diseases such as rheumatoid arthritis. Advanced computer-aided drug design techniques, such as pharmacophore and 3D-QSAR modeling, were used. Two strong 3D-QSAR models were created, and their predictive power was validated by the strong correlation (R2 values > 80%) between the predicted and experimental activity. With an ROC value of 0.9, a pharmacophore model grounded in the DHRRR hypothesis likewise demonstrated strong predictive ability. Eight possible inhibitors were found, and six new inhibitors were designed in silico using these computational models. The pharmacokinetic and safety characteristics of these candidates were thoroughly assessed. The possible interactions between the inhibitors and the target enzymes were made clear via molecular docking. Furthermore, MM/GBSA computations and molecular dynamics simulations offered insightful information about the stability of the binding between inhibitors and CYP3A4 or JAK3. Through the integration of various computational approaches, this study successfully identified potential inhibitor candidates for additional investigation and efficiently screened compounds. The findings contribute to our knowledge of enzyme–inhibitor interactions and may help us create more effective treatments for autoimmune conditions like rheumatoid arthritis.