Piraxostat

Xanthine Oxidase (XO), that catalyzes the oxidation of purine bases to uric acid with the generation of reactive oxygen species, is a key enzyme in the pathogenesis of hyperuricemia, gout and cardiovascular diseases.Xanthine Oxidase inhibitors for anti hyperuricemic therapy have been mainly employed for the treatment of gout.In the present research, mol. modeling investigations, such as CoMFA, Tpomer CoMFA, CoMSIA and HQSAR, mol. docking and mol. dynamics (MD) simulations were carried out on a series of pyrimidine derivatives as XO inhibitors.The performance and predictive capabilities of generated models were evaluated by internal and external validation techniques.The CoMFA (q2, 0.799;r2ncv, 0.948; r2pred,0.916), Topomer CoMFA (q2, 0.882;r2ncv, 0.914; r2pred,0.926), CoMSIA (q2, 0.772;r2ncv, 0.956; r2pred,0.927) and HQSAR models (q2, 0.895;r2ncv, 0.954; r2pred,0.921) for training and test set of XO inhibition yielded significant statistical findings.Several external parameters, such as,Q2F1,Q2F2,Q2F3and CCC were 0.928, 0.924, 0.784 and 0.959 (CoMFA); 0.926, 0.923, 0.779 and 0.959 (Topomer-CoMFA); 0.927, 0.915, 0.781 and 0.961 (CoMSIA) and 0.921, 0.920, 0.762 and 0.963 (HQSAR), resp.Therefore, such QSAR models were perfect, strong with better predictability.Contour maps of all models were generated and proved by mol. docking studies and mol. dynamics simulation, that the steric, hydrophobic and hydrogen bonding fields are crucial in these models for improving the binding affinity and determine of structure- activity relationship.These theor. results are possibly beneficial to design new strong XO inhibitors with enhanced activity to treat hyperuricemia and gout.