Güzel Yahya, Karakaya Sevcan, Wang Lichang, Türkmenoğlu Burçin, Kızılcan Dilek Şeyma
Department of Chemistry, Faculty of Science, Erciyes University, Kayseri 38280, Türkiye.
Department of Chemistry, Faculty of Science, Erciyes University, Kayseri 38280, Türkiye.
Comput Biol Chem. 2025 Oct;118:108489. doi: 10.1016/j.compbiolchem.2025.108489. Epub 2025 Apr 27.
The understanding of the interaction mechanism between ligands and receptors depends on the performance of the descriptors. In this study, the electrophilic and nucleophilic interactions of diarylpyrazole-benzenesulfonamide derivatives active on human carbonic anhydrase in 3D space were analyzed using different types of Local Reactivity Descriptors (LRDs). Three different classes of descriptors used in the Molecular Conformer Electron Topology (MCET) method: (1) Atomic charge, (2) Frontier Molecular Orbital (FMO) and (3) Fukui and Klopman indices. To assess the effect of changing LRD types on the ligand side, the variations in dimensions and values of the parameters on the receptor side were calculated for 3D quantitative structure-activity relationship (3D-QSAR) models. Each model was evaluated using the Leave One Out-Cross Validation (LOO-CV) method on the training set from the split molecule series and then validated on the external test set. As a result of comparing the different LRD types, a model with satisfactory values of Q = 0.933 and R = 0.964 was selected, which consisted of the electrostatic charge and LUMO coefficient under the Klopman Index (K_I) class. The activity changes at the interaction points between the ligand and receptor (L-R) were plotted to show the Auxiliary Group (AG) and Anti Pharmacophore Shielding (APS) groups. In addition to ligand-based drug design, the binding interactions between the ligand and the identified targets were investigated through molecular docking, one of the most widely used methods in structure-based drug design.
对配体与受体之间相互作用机制的理解取决于描述符的性能。在本研究中，使用不同类型的局部反应性描述符（LRD）分析了在三维空间中对人碳酸酐酶有活性的二芳基吡唑-苯磺酰胺衍生物的亲电和亲核相互作用。分子构象电子拓扑（MCET）方法中使用的三类不同描述符：（1）原子电荷，（2）前线分子轨道（FMO）和（3）福井和克洛普曼指数。为了评估改变LRD类型对配体方面的影响，针对三维定量构效关系（3D-QSAR）模型计算了受体方面参数的维度和值的变化。每个模型在拆分分子系列的训练集上使用留一法交叉验证（LOO-CV）方法进行评估，然后在外部测试集上进行验证。通过比较不同的LRD类型，选择了一个Q = 0.933和R = 0.964值令人满意的模型，该模型由克洛普曼指数（K_I）类下的静电荷和最低未占分子轨道系数组成。绘制配体与受体（L-R）相互作用点处的活性变化以显示辅助基团（AG）和反药效团屏蔽（APS）基团。除了基于配体的药物设计外，还通过分子对接研究了配体与已鉴定靶点之间的结合相互作用，分子对接是基于结构的药物设计中使用最广泛的方法之一。
