Tahiroğlu Veysel, Gören Kenan, Bağlan Mehmet
Nursing Department, Health Sciences Faculty, Şırnak University, Şırnak, Turkey.
Department of Chemistry, Faculty of Science and Letters, Kafkas University, Kars, Turkey.
BMC Pharmacol Toxicol. 2025 Jun 4;26(1):116. doi: 10.1186/s40360-025-00958-4.
In this study, the structural, electronic, pharmacokinetic, and biological properties of molecule 2-(6-kloro-2-(4-klorofenil)imidazo[1,2-a]piridin-3-il)-N, N-dipropilasetamid (Alpidem), an imidazopyridine derivative anxiolytic known for its high BZ₁ (benzodiazepine-1) receptor affinity and low adverse effect profile, were comprehensively investigated by density functional theory (DFT) and in-silico methods. The alpidem molecule was optimized using the 6-311G(d, p) basis set with the B3LYP and B3PW91 methods; information on the stability and chemical reactivity of the structure was obtained via the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), molecular electrostatic potential (MEP) maps, natural bonding orbital (NBO) analysis, non-linear optical (NLO) properties, and Mulliken charge distributions. Comparative analysis of two different methods has shown that the results are consistent with each other and provide reliable data. In addition, the drug similarity, bioavailability score, bioactivity values, absorption, distribution, metabolism, and excretion (ADME) profiles of the Alpidem molecule were calculated, and it was determined that the Alpidem molecule has pharmacologically favorable properties. Within the scope of molecular docking analyses, its interactions with two different enzymes (PDB ID: 2Z5X and 4BDT) associated with Alzheimer's disease were evaluated. The binding energy values obtained were - 8.00 kcal/mol (2Z5X) and - 9.60 kcal/mol (4BDT), respectively, and the strong binding affinity, especially with the 4BDT protein, suggests that Alpidem may be a potential inhibitor candidate in Alzheimer's disease. This multi-level theoretical study demonstrates that Alpidem is a drug repurposing molecule not only as an anxiolytic but also in neurodegenerative diseases and provides important data that will shed light on experimental studies. The results of this multi-level theoretical study show that Alpidem is a drug repurposing molecule not only as an anxiolytic but also in neurodegenerative diseases and provides important data that will shed light on experimental studies.
在本研究中，通过密度泛函理论（DFT）和计算机模拟方法，对分子2-(6-氯-2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基)-N,N-二丙基乙酰胺（阿普地尔）的结构、电子、药代动力学和生物学性质进行了全面研究。阿普地尔是一种咪唑并吡啶衍生物抗焦虑药，以其对BZ₁（苯二氮䓬-1）受体的高亲和力和低不良反应谱而闻名。使用6-311G(d,p)基组和B3LYP及B3PW91方法对阿普地尔分子进行了优化；通过最高占据分子轨道（HOMO）、最低未占据分子轨道（LUMO）、分子静电势（MEP）图、自然键轨道（NBO）分析、非线性光学（NLO）性质和 Mulliken 电荷分布获得了有关该结构稳定性和化学反应性的信息。对两种不同方法的比较分析表明，结果相互一致并提供了可靠的数据。此外，计算了阿普地尔分子的药物相似性、生物利用度评分、生物活性值、吸收、分布、代谢和排泄（ADME）谱，并确定阿普地尔分子具有药理学上有利的性质。在分子对接分析范围内，评估了其与两种与阿尔茨海默病相关的不同酶（PDB ID：2Z5X和4BDT）的相互作用。获得的结合能值分别为-8.00千卡/摩尔（2Z5X）和-9.60千卡/摩尔（4BDT），尤其是与4BDT蛋白的强结合亲和力表明阿普地尔可能是阿尔茨海默病的潜在抑制剂候选物。这项多层次的理论研究表明，阿普地尔不仅是一种可重新利用的抗焦虑药物，而且在神经退行性疾病方面也是如此，并为实验研究提供了重要数据。这项多层次理论研究的结果表明，阿普地尔不仅是一种可重新利用的抗焦虑药物，而且在神经退行性疾病方面也是如此，并为实验研究提供了重要数据。
