Computational Investigation of Hardwickiic Acid-Derived Amides as Potential Cholinesterase Inhibitors: Molecular Docking and ADME/Tox Predictions

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2025-07-02 DOI:10.1016/j.cbi.2025.111631

Rayssa Ribeiro , Franco H.A. Leite , Géssica O. Mendes , Fernanda Georgia de F. T. Barbosa , Samir F.A. Cavalcante , Tanos C.C. Franca , Marcelo C. Santos , Valdir F. Veiga-Junior

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Abstract

This study is a theoretical investigation of amides derived from hardwickiic acid (HA) as potential inhibitors of human acetyl- and butyryl-cholinesterase (hAChE and hBChE) and as drug candidates against Alzheimer's Disease (AD). Twelve compounds were prepared and geometrically optimized using GaussView 5.0.8 and the DFT method with the B3LYP/6-31G basis set to visualize molecular electrostatic potential (MEP) maps and frontier orbitals (HOMO and LUMO). In addition, pharmacokinetic and toxicological properties were studied using the online servers PreADMET and SwissADME. Molecular docking was performed against crystal structures of hAChE and hBChE prepared with the biopolymer module in SYBYL-X 2.0, previously validated. The results revealed similar profiles in surface maps and molecular orbitals for the amide substituent group. Pharmacokinetic predictions demonstrated that all 12 HA amide derivatives showed significant values for blood-brain barrier (BBB) penetration, classifying them as active in the central nervous system (CNS), a crucial pathway for AD treatment. Intermolecular interactions between the compounds and targets suggest that the benzyl amide derivative I had the highest affinity toward the hAChE binding site (−10.1 kcal/mol), while the hydroxy amide derivative L showed the highest affinity for the hBChE binding site (−9.7 kcal/mol). These findings can inform future enzymatic assays of HA amide derivatives against AChE and BChE.

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硬酸衍生酰胺的分子对接计算研究和ADME/Tox特性预测作为胆碱酯酶抑制剂的潜力。

本研究是一项从硬脂酸（HA）衍生的酰胺作为人类乙酰和丁基胆碱酯酶（hAChE和hBChE）的潜在抑制剂和阿尔茨海默病（AD）候选药物的理论研究。利用GaussView 5.0.8和DFT方法对12个化合物进行了几何优化，设置B3LYP/6-31G基，以显示分子静电势（MEP）图和前沿轨道（HOMO和LUMO）。此外，利用在线服务器PreADMET和SwissADME研究了其药代动力学和毒理学特性。在SYBYL-X 2.0中使用生物聚合物模块制备的hAChE和hBChE的晶体结构进行了分子对接，并进行了先前的验证。结果显示酰胺取代基的表面图和分子轨道相似。药代动力学预测表明，所有12种HA酰胺衍生物都具有显著的血脑屏障（BBB）穿透价值，将它们分类为在中枢神经系统（CNS）中具有活性，中枢神经系统是治疗AD的关键途径。化合物与靶点的分子间相互作用表明，苯基酰胺衍生物I对hAChE结合位点的亲和力最高（-10.1 kcal/mol），羟基酰胺衍生物L对hBChE结合位点的亲和力最高（-9.7 kcal/mol）。这些发现可以为未来HA酰胺衍生物对AChE和BChE的酶促测定提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.