Llanes Luana C, Kuehlewein Isabelle, França Igor V de, da Silva Luana Veiga, da Cruz Junior José W
Department of Chemistry and Biochemistry, University of California Santa Barbara, California 93106, USA.
Department of Exact Sciences and Education, Technologic, Exact Sciences and Education Center, Federal University of Santa Catarina, Blumenau, Brazil.
Curr Med Chem. 2023;30(6):701-724. doi: 10.2174/0929867329666220803113411.
Alzheimer's disease (AD) is a progressive neurodegenerative disease that compromises the cognitive system and causes dementia. In general, AD affects people over 65 years old, which implies a social impact if we consider future projections due to the increase in life expectancy. The drugs currently marketed only slow the progression of the disease. In this sense, the search for new drugs is a relevant topic in medicinal chemistry. The therapeutic strategy adopted herein is the cholinergic hypothesis, for which acetylcholinesterase enzyme (AChE) inhibitors constitute the main treatment for the disease.
This review compiles research in synthetic and natural compounds with AChE inhibitory function.
Data were collected based on investigations of AChE inhibitors in the last 5 years of the 2010 decade. Synthetic and natural compounds were investigated, for which Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD) strategies were performed to better understand the structure-activity relationship of promising therapeutic agents.
Prediction of physicochemical and pharmacokinetic properties used to calculate the bioavailability radar, lipophilicity, drug-likeness, and pharmacokinetics parameters (SwissADME) indicated that most active compounds are associated with the following characteristics: molecular weight above 377 g/mol; molar refractivity over 114; fraction Csp3 below 0.39 and TPSA above 43 Å. The most active compounds had a lipophilicity parameter in the range between 2.5 and 4.52, a predominating lipophilic character. Atoms and bonds/interactions relevant for drug development were also investigated and the data pointed out the following tendencies: number of heavy atoms between 16 and 41; number of aromatic heavy atoms between 6 and 22; number of rotatable bonds between 1 and 14; number of H-bond acceptors between 1 and 11; number of H-bond donors below 7. Molecular docking studies indicated that all compounds had higher Goldscores than the drugs used as a positive control, indicating a stronger interaction with the enzyme.
The selected compounds represent a potential for new anticholinesterase drugs and may be good starting-point for the development of new candidates. Also, design rules can be extracted from our analysis.
阿尔茨海默病（AD）是一种渐进性神经退行性疾病，会损害认知系统并导致痴呆。一般来说，AD影响65岁以上的人群，如果考虑到预期寿命增加带来的未来预测，这意味着会产生社会影响。目前市面上的药物只能减缓疾病的进展。从这个意义上讲，寻找新药是药物化学中的一个重要课题。本文采用的治疗策略是胆碱能假说，为此乙酰胆碱酯酶（AChE）抑制剂构成了该疾病的主要治疗方法。
本综述汇编了具有AChE抑制功能的合成化合物和天然化合物的研究。
基于对2010年代最后5年AChE抑制剂的研究收集数据。对合成化合物和天然化合物进行了研究，采用基于配体的药物设计（LBDD）和基于结构的药物设计（SBDD）策略，以更好地理解有前景的治疗药物的构效关系。
用于计算生物利用度雷达、亲脂性、类药性和药代动力学参数（SwissADME）的理化和药代动力学性质预测表明，大多数活性化合物具有以下特征：分子量高于377 g/mol；摩尔折射率超过114；Csp3分数低于0.39且拓扑极性表面积（TPSA）高于43 Å。最具活性的化合物的亲脂性参数在2.5至4.52之间，具有主要的亲脂性特征。还研究了与药物开发相关的原子和键/相互作用，数据指出了以下趋势：重原子数在16至41之间；芳香重原子数在6至22之间；可旋转键数在1至14之间；氢键受体数在1至11之间；氢键供体数低于7。分子对接研究表明，所有化合物的Gold分数均高于用作阳性对照的药物，表明与该酶的相互作用更强。
所选化合物代表了新型抗胆碱酯酶药物的潜力，可能是开发新候选药物的良好起点。此外，我们的分析可以提取设计规则。
