A molecular approach in drug development for Alzheimer’s disease

• Published in: Biomedicine & pharmacotherapy Vol. 106; pp. 553 - 565
• Main Authors: Agatonovic-Kustrin, Snezana, Kettle, Christine, Morton, David W.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.10.2018
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; AChE inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Alzheimer’s disease; Animals; Binding Sites; Brain - drug effects; Brain - enzymology; Brain - pathology; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - pharmacology; Drug Design; Drug Therapy, Combination; Dual binding ligands; Excitatory Amino Acid Antagonists - pharmacology; Fusing approach; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - chemistry; GPI-Linked Proteins - metabolism; Humans; Hybrid molecules; Ligands; Linking strategy; Molecular Targeted Therapy - methods; Monoamine Oxidase Inhibitors - pharmacology; MTDL; Nootropic Agents - chemistry; Nootropic Agents - metabolism; Nootropic Agents - pharmacology; Pharmacophore; Protein Conformation; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship; Fusing approach; Linking strategy; Alzheimer’s disease; AChE inhibitors; Dual binding ligands; MTDL; Pharmacophore; Hybrid molecules
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.06.147

[Display omitted] •Current single target FDA approved drugs only provide symptomatic treatments.•Dual binding AChE inhibitors can positively modify the course of the AD pathogenesis.•Pharmacophores of approved therapeutics are combined into hybrid molecules.•Step-wise addition of pharmacophores leads to multi target lead-like molecules.•Multi-Target-Directed Ligands can simultaneously modulate multiple biological targets. An increase in dementia numbers and global trends in population aging across the world prompts the need for new medications to treat the complex biological dysfunctions, such as neurodegeneration associated with dementia. Alzheimer’s disease (AD) is the most common form of dementia. Cholinergic signaling, which is important in cognition, is slowly lost in AD, so the first line therapy is to treat symptoms with acetylcholinesterase inhibitors to increase levels of acetylcholine. Out of five available FDA-approved AD medications, donepezil, galantamine and rivastigmine are cholinesterase inhibitors while memantine, a N-methyl d-aspartate (NMDA) receptor antagonist, blocks the effects of high glutamate levels. The fifth medication consists of a combination of donepezil and memantine. Although these medications can reduce and temporarily slow down the symptoms of AD, they cannot stop the damage to the brain from progressing. For a superior therapeutic effect, multi-target drugs are required. Thus, a Multi-Target-Directed Ligand (MTDL) strategy has received more attention by scientists who are attempting to develop hybrid molecules that simultaneously modulate multiple biological targets. This review highlights recent examples of the MTDL approach and fragment based strategy in the rational design of new potential AD medications.