Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution

Abstract

Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments.

Beware of docking!

“…That is all, and nothing else. Some papers claim that a well-docked ligand indicates that it is a strong agonist or inhibitor [40][41][42][43]. Of course we will not know if it is an agonist or inhibitor until we perform further validation of bioassays.…”

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…Their results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects [194]. However, all these findings are in the primitive stage, so there is a need to search for H3R antagonists to treat the AD patients in an early stage as the histamine plays a crucial role in oxidative stress and inflammation, and there is also a need to the check the efficacy and tolerability of novel H3R antagonists [195] including pitolisant [191] in AD mouse models and patients.…”

Procognitive Properties of Drugs with Single and Multitargeting H3 Receptor Antagonist Activities

“…Results obtained from our previous theoretical studies, pharmacophore modeling, design , synthesis, and biological evaluation of novel compounds should be further used in discovery of novel dual‐activity hH 3 R antagonists/inverse agonists with procognitive effect.…”