Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study

• Published in: International journal of molecular sciences Vol. 22; no. 15; p. 8122
• Main Authors: Zhai, Na, Wang, Chenchen, Wu, Fengshou, Xiong, Liwei, Luo, Xiaogang, Ju, Xiulian, Liu, Genyan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.07.2021; MDPI
• Subjects: 3D-QSAR; Binding; Carboxylic acids; Carboxylic Acids - chemistry; docking; Drug Design; Dynamic structural analysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; Humans; Hydrogen Bonding; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Hyperuricemia; Hyperuricemia - drug therapy; Inhibitors; Molecular docking; Molecular Docking Simulation - methods; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Nitrogen; Pharmacology; pharmacophore; Protein Binding; Quantitative Structure-Activity Relationship; Rheumatism; Structure-activity relationships; Uric acid; virtual screening; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - chemistry; xanthine oxidase inhibitor; 3D-QSAR; docking; xanthine oxidase inhibitor; virtual screening; pharmacophore
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22158122

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q = 0.897, R = 0.983, r = 0.948 in a CoMFA model, and q = 0.922, R = 0.990, r = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.