Title:Anticholinesterase Agents For Alzheimer's Disease Treatment: An Updated
Overview
Volume: 30
Issue: 6
关键词:
阿尔茨海默病 (AD)、AChE 抑制剂、分子对接、构效关系 (SAR)、基于结构的药物设计 (SBDD)、基于配体的药物设计 (LBDD)、药代动力学。
摘要:
Background: 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.
Objective: This review compiles research in synthetic and natural compounds with
AChE inhibitory function.
Methods: 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.
Results: 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 Å2. 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.
Conclusion: 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.
