In silico studies of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide derivatives as potent TRPV1 antagonists using 3D QSAR, ADMET and Molecular Docking

Abstract TRPV1 is a promising therapeutic target given its involvement in pain management and inflammation. TRPV1 antagonists are increasingly sought after for their analgesic, anti-inflammatory and antitumor properties with fewer side effects. This study focused on the design of new effective TRPV1 antagonists by replacing the pyridine ring of BCTC with a pyrimidine ring. Significant 3D-QSAR models were developed using CoMSIA and CoMFA methods and showed a satisfactory correlation between experimental and predicted activity (Q2 = 0.715; R2 = 0.988; SEE = 0.048). Electrostatic, hydrophobic fields and hydrogen bond acceptors contributed significantly to the biological activity of studied compounds. Molecular docking analysis validated the 3D-QSAR models and explained the interactions of the most active ligands with the binding site. These results permitted prediction of new compounds, whose pharmacokinetic properties, toxicity and pharmacodynamics effects were assessed using ADMET and drug similarity.