Computationally exploring novel xanthine oxidase inhibitors using docking-based 3D-QSAR, molecular dynamics, and virtual screening
Several novel series of xanthine oxidase (XO) inhibitors (XOIs) with nitrogen-containing heterocycles have been reported recently. To better comprehend the three-dimensional quantitative structure-activity relationships (3D-QSAR) and mechanisms of action of these novel XOIs, in this study, a systematic modeling study was performed on 53 XOIs with diverse structures using the docking-based 3D-QSAR, virtual screening, and molecular dynamics (MD) methods. The docking results revealed that these XOIs could form the hydrogen bonds, π-π stackings, and hydrophobic interactions in the binding site of XO, which might be important for maintaining their inhibitory activities. The 3D-QSAR models, comprising the comparative molecular field analysis (q2 = 0.741, R2 = 0.988, and rpred2 = 0.940), comparative molecular similarity indices analysis (q2 = 0.846, R2 = 0.982, and rpred2 = 0.916), and Topomer CoMFA (q2 = 0.947, R2 = 0.983, and rpred2 = 0.909) models, exhibited satisfying quality and excellent predictive ability. Six XOI hit compounds (N1-N6) with higher docking-scores and better predicted activities were obtained by the virtual screening. The MD results indicated that compound N6 could stably bind with the XO and might be a promising XOI candidate. This study could provide useful information and theoretical guidance for the design and development of novel XOIs.