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.

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.

Computational pharmaceutical analysis of anti-Alzheimer's Chinese medicine Coptidis Rhizoma alkaloids.

Alzheimer's disease (AD) is an age-related neurodegenerative disease, affecting over 20 million people worldwide. Until recently, two major hypotheses were proposed regarding the molecular mechanism of pathogenesis: the cholinergic hypothesis and the amyloid cascade hypothesis. At present, acetylcholinesterase inhibitors are the most effective therapy for AD. Most pharmacological research has focused on the ability of acetylcholinesterase to alleviate cholinergic deficit and improve neurotransmission. Coptidis rhizoma and its isolated alkaloids are reported to possess a variety of activities, including neuroprotective and antioxidant effects. However, as yet no theoretical analysis exists to support this hypothesis. To examine this theory, we applied a computational pharmaceutical analysis to reveal that Chinese medicine Coptidis rhizoma alkaloids have much higher activities than Donepezil (commercial name is Aricept) by docking and scoring.

Computational analysis of de novo evolution of hepatitis C virus NS5B polymerase inhibitors.

HCV (Hepatitis C virus) that causes chronic liver disease. HCV NS5B RNA-dependent RNA polymerase (RbRp) and NS3 protease are able to affect virtual replication of genes. Computer-aided drug design (CADD) aims at designing new molecules with pharmacological activity. In this study, we used the Discovery Studio 2.0 program and the scoring function to estimate the Dock Score, piecewise linear potential 1 (PLP1), piecewise linear potential 2 (PLP2), and potential of mean force (PMF) score of novel compounds. In this way, novel compounds with "de novo evolution" can be found. Using the the pharmacophore features that are near the receptor pocket and the score functions to calculate scores for the ligand-receptor interaction, the new ligands were selected, developed and virtually placed in the binding site of the receptor. A new compound, EVO12, gave the best score, indicating that it may be an efficient polymerase inhibitor of HCV NS5B.