Division of Applied Life Science, Systems and Synthetic Agrobiotech Center, Research Institute of Natural Science, Gyeongsang National University, Gazha-dong, Jinju, Republic of Korea.
Acta Pharmacol Sin. 2012 Jul;33(7):964-78. doi: 10.1038/aps.2012.21. Epub 2012 Jun 11.
To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function.
Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory.
Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1.
This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.
确定对丁酰胆碱酯酶（BChE）功能抑制有贡献的关键化学特征，具有可靠的几何约束。
基于配体的药效团模型用于确定 BChE 抑制剂的关键化学特征。使用各种技术（例如 Fischer 随机化方法、测试集和诱饵集）验证生成的药效团模型。最佳药效团模型被用作虚拟筛选中的查询，以识别抑制 BChE 的新型支架。通过虚拟筛选中最佳假设选择的化合物被测试其药物样性质，并应用分子对接研究确定命中化合物在 BChE 活性部位的最佳取向。为了确定命中化合物的反应性，使用密度泛函理论进行前沿轨道分析。
基于其相关系数（0.96）、均方根（RMS）偏差（1.01）和总费用（105.72），选择包含 2 个 HBA、1 个 Hy-Ali 和 1 个 Hy-Ar 的定量假设 Hypo1 作为最佳假设。因此，Hypo1 被用作 Maybridge 和 Chembridge 数据库虚拟筛选的 3D 查询。通过 ADMET、Lipinski 五规则和分子对接对命中化合物进行过滤，以减少假阳性结果的数量。最后，根据它们与 BChE 活性部位重要氨基酸的关键相互作用，基于 33 种化合物被选中。为了确认抑制剂的效力，计算了命中化合物和 7 种训练集化合物的轨道能量，如 HOMO 和 LUMO。在 33 种命中化合物中，选择了具有最高 HOMO 值的 10 种化合物，并且根据对稳定性和能量转移很重要的能量间隙，进一步从该组中剔除 5 种化合物。从总体结果来看，确认 5 种命中化合物是潜在的 BChE 抑制剂，它们满足 Hypo1 中的所有药效团特征。
本研究确定了对 BChE 活性抑制有贡献的具有几何约束的重要化学特征。选择 5 种化合物作为最佳命中 BchE 抑制化合物。
