Arabi Alya A
College of Medicine and Health Sciences, Department of Biochemistry and Molecular Biology, United Arab Emirates University, AlAin, P.O. Box: 15551, United Arab Emirates.
ACS Omega. 2025 Aug 5;10(32):36216-36220. doi: 10.1021/acsomega.5c04043. eCollection 2025 Aug 19.
Solvent effects influence the electronic properties of drug-like molecules, including their behavior in bioisosteric design. This study investigates the impact of hydrophobic environments, modeled using the solvation model based on density (SMD), on the average electron density (AED) values of 63 bioisosteric moieties of carboxylic acid. Dipole moments and AED values were computed at the B3LYP-D3-(BJ)/6-311++G-(d,p) level of theory, followed by atom in molecule analysis. The AED values remained consistent, irrespective of the dielectric constant of the hydrophobic medium. These findings support the applicability of the AED tool for evaluating bioisosterism even in nonpolar environments such as the interior of a protein. Furthermore, solvent-induced changes in AED were evaluated under polar and nonpolar solvation, using the SMD model versus the integral equation formalism polarizable continuum model (IEFPCM). Results show that both models yield comparable AED values and, thus, either is suitable for studying AED while accounting for solvent effects.
溶剂效应会影响类药物分子的电子性质，包括它们在生物电子等排体设计中的行为。本研究使用基于密度的溶剂化模型（SMD）模拟疏水环境，研究其对63种羧酸生物电子等排体基团平均电子密度（AED）值的影响。在B3LYP-D3-(BJ)/6-311++G-(d,p)理论水平上计算偶极矩和AED值，随后进行分子中的原子分析。无论疏水介质的介电常数如何，AED值均保持一致。这些发现支持了AED工具即使在诸如蛋白质内部等非极性环境中评估生物电子等排体的适用性。此外，使用SMD模型与积分方程形式极化连续介质模型（IEFPCM），在极性和非极性溶剂化条件下评估了溶剂诱导的AED变化。结果表明，这两种模型产生的AED值相当，因此，在考虑溶剂效应时，两者都适用于研究AED。
