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 q² = 0.897, R² = 0.983, r_pred² = 0.948 in a CoMFA model, and q² = 0.922, R² = 0.990, r_pred² = 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.

中文翻译：

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通过综合计算机研究探索基于 1,6-二氢嘧啶-5-羧酸的新型黄嘌呤氧化酶抑制剂


黄嘌呤氧化酶（XO）是有效治疗高尿酸血症相关疾病的重要靶点。最近报道了一系列新型2-取代6-氧代-1,6-二氢嘧啶-5-羧酸（ODC）作为XO抑制剂（XOI），具有显着的活性。为了更好地了解这些XOIs的关键药理特征并探索更多的热门化合物，在本研究中，三维定量构效关系（3D-QSAR）、分子对接、药效团建模和分子动力学（MD）研究在 46 个 ODC 上进行。构建的3D-QSAR模型表现出可靠的可预测性和令人满意的验证参数，包括CoMFA模型中的q ² = 0.897，R ² = 0.983，r _pred ² = 0.948，以及q ² = 0.922，R ² = 0.990，r _pred ² = CoMSIA 模型中为 0.840。对接和 MD 模拟进一步深入了解了这些 ODC 与 XO 蛋白的结合模式。结果表明，关键残基 Glu802、Arg880、Asn768、Thr1010、Phe914 和 Phe1009 可以通过氢键、π-π 堆积或疏水相互作用与 ODC 相互作用，这可能对这些 XOI 的活性具有重要意义。使用构建的药效团模型结合分子对接和 ADME 预测，虚拟筛选出了四个潜在的命中。通过 MD 模拟还发现这四个命中在结合口袋中相对稳定。本研究结果可能为新型XOI的设计和开发提供有效信息。