2024

Abdelilah Toughzaoui; Oussama Chedadi; Abdellah El Aissouq; Youssef El Ouardi; Mohammed Bouachrine; kamal Moradi; Abdelkrim Ouammou

TRPV4 antagonists that could be potential drugs for treatment and management of neuropathic pain. This study was conducted to systematically design several amino derivatives of 2,4'-dimethyl-[4,5'-bithiazol]-2-yl as antagonists. In silico computational methods, such as 3D quantitative structure-activity relationship modeling (3D-QSAR), molecular docking, and pharmacokinetic property assessment (ADMET), were used to discover new compounds with strong antagonistic activity. The best-performing 3D-QSAR model was developed using a partial least squares approach and comparative molecular similarity analysis (CoMSIA). The developed model demonstrated an excellent ability to correlate and predict properties (R2 = 0.932, Q2 = 0.620, and SEE = 0.109). It was observed that variations in biological activity were significantly influenced by interactions with steric, electrostatic, and hydrophobic fields. Molecular docking was used to validate the 3D-QSAR methods and to explain the binding site and interactions between the most active ligands and the receptor. Based on these results, a new series of compounds was predicted. The best-anchored molecules underwent MD simulation to confirm their dynamic behavior and stability, and they also underwent retrosynthetic analysis to assist in their synthesis.