Investigation of pyrimidine analogues as xanthine oxidase inhibitors to treat of hyperuricemia and gout through combined QSAR techniques, molecular docking and molecular dynamics simulations

Abdizadeh, Rahman and Heidarian, Esfandiar and Hadizadeh, Farzin and Abdizadeh, Tooba (2020) Investigation of pyrimidine analogues as xanthine oxidase inhibitors to treat of hyperuricemia and gout through combined QSAR techniques, molecular docking and molecular dynamics simulations. Journal of the Taiwan Institute of Chemical Engineers, 113. pp. 72-100. ISSN 18761070

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Abstract

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, molecular modeling investigations, such as CoMFA, Tpomer CoMFA, CoMSIA and HQSAR, molecular docking and molecular 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 (q(2) , 0.799; r(ncv)(2), 0.948; r(pred)(2) 0.916), Topomer CoMFA (q(2) , 0.882; r(ncv)(2) 0.914; r(pred)(2) , 0.926), CoMSIA (q(2) , 0.772; r(ncv)(2) 0.956; r(pred)(2) , 0.927) and HQSAR models (q(2) , 0.895; r(ncv)(2) , 0.954; r(pred)(2) , 0.921) for training and test set of XO inhibition yielded significant statistical findings. Several external parameters, such as, Q(F1)(2), Q(F2)(2), Q(F)(3)(2) and 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), respectively. Therefore, such QSAR models were perfect, strong with better predictability. Contour maps of all models were generated and proved by molecular docking studies and molecular 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 theoretical results are possibly beneficial to design new strong XO inhibitors with enhanced activity to treat hyperuricemia and gout. (C) 2020 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved. Keywords:Xanthine oxidase; QSAR; Pyrimidine; Molecular docking; Molecular dynamics simulations

Item Type: Article
Subjects: QU Biochemistry
Divisions: Faculty of Medicine > Basic Sciences Academic Groups > Department of Parasitology and Mycology
Depositing User: zeynab . bagheri
Date Deposited: 07 Nov 2020 10:16
Last Modified: 11 Nov 2020 04:20
URI: http://eprints.skums.ac.ir/id/eprint/8702

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