Design of Multifunctional H3 Receptor Inverse Agonists with Ache Inhibitor Activity for Treatment of Alzeihmer’s Disease

Acetyl cholinesterase (AchE) and N-methyl-D-aspartate antagonists are at present the only commercially available treatment for Alzheimer's disease (AD). Histamine H3 receptor antagonists are used for the treatment of several neurodegenerative disorders such as Epilepsy, Alzheimer‘s and Parkinson‘s diseases. Both H3 and AchE inhibitors alleviate the symptoms of Alzheimer’s disease by enhancing the acetylcholine levels in the brain but the mechanism of action involved in both the cases is different. Here, it is proposed that histamine H3 antagonist with AchE inhibitor activity can be used as a novel class of drugs to treat Alzheimer‘s disease with lesser adverse peripheral effects than excessive AchE inhibitor alone. Thus the main objective of this work is to design multifunctional inhibitors for reduction of the side effects of the already available drugs. This study is divided into two parts. In the first part, homology modeled structure of histamine H3 active site and available crystal structure of AchE was used to collect the information for identification of pharmacophore. The important descriptors were identified based on comparative 2D-QSAR and 3D-QSAR study of 28 drug-like compounds for histamine H3 receptors collected from the literature. In the second part, five hybrid molecules were generated based on the pharmacophore of histamine H3 receptor and known pharmacophore of AchE inhibitors. All five hybrid molecules were screened through ADME/Tox filters. The hybrid molecule was validated through GOLD docking score in both AchE and histamine H3 receptors. The best hybrid compound was then evaluated by molecular dynamics (MD) simulation in water solvent model using 3D model of human histamine H3 receptor (build based on bovine rhodopsin structure).