Benzodioxol Group Driving Supramolecular Arrangement of Two Tri-Methoxy Chalcones onto Β-Secretase 1 Enzyme Active Site

Chalcones are compounds with wide interesting biological activities including Alzheimer’s disease. A comparative study was performed between the chalcones (E)-1-(2-aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and 1-(6-amino-1,3-benzodioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one regarding the influence of benzodioxol group on their molecular conformations. The first chalcone was neutralized with dilute hydrochloric acid, while solid of the second was filtered and recrystallized from ethanol, both on centrosymmetric space group P21/c. Their molecular packing were evaluated by Hirshfeld surfaces, and both frontier molecular orbitals and molecular electrostatic potential (MEP) map were carried out by density functional theory (DFT) calculations. The compounds are stabilized by C–H…O and C–H…p interactions, as observed on MEP map, while the HOMO-LUMO gap indicated the conformational stability. The pharmacophore mapping approach was carried out for the identification of potential target candidates and then, further molecular docking analysis targeting the beta-secretase 1 (BACE-1) protein as a tactic to develop potential AD inhibitors, was performed. The AutoDock Vina score in redocking result for 2OHQ is –7.4 and –7.6 kcal moL-1. Additionally, the docking results for compounds inside the active site of the 2OHQ structure showed that both compounds bound to the BACE-1 active site with AutoDock Vina score of –6.0 kcal moL-1.

查尔酮（Chalcones）是一类具有多样生物活性的化合物，其活性涵盖针对阿尔茨海默病（Alzheimer’s disease）的干预作用。本研究针对两种查尔酮——(E)-1-(2-氨基苯基)-3-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮与1-(6-氨基-1,3-苯并二氧杂环戊烯-5-基)-3-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮——开展对比分析，旨在探究苯并二氧杂环戊烯基团对其分子构象的影响。第一种查尔酮经稀盐酸中和处理，第二种查尔酮固体则经过滤后从乙醇中重结晶，二者均结晶于中心对称空间群P2₁/c。研究通过希施费尔德表面（Hirshfeld surfaces）评估了两种化合物的分子堆积模式，并借助密度泛函理论（DFT）计算，完成了前沿分子轨道与分子静电势（MEP）图谱的构建。正如分子静电势图谱所观测到的，两类化合物通过C–H…O与C–H…π相互作用实现分子稳定；而HOMO-LUMO能隙则可反映其构象稳定性。本研究采用药效团映射法识别潜在药物作用靶点，随后以β-分泌酶1（BACE-1）蛋白为靶点开展分子对接分析，以期开发潜在的阿尔茨海默病抑制剂。2OHQ的重新对接AutoDock Vina评分分别为–7.4与–7.6 kcal·mol⁻¹。此外，两种化合物在2OHQ结构活性口袋内的对接结果显示，二者均结合于BACE-1的活性位点，AutoDock Vina评分为–6.0 kcal·mol⁻¹。