One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug

Abstract

HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design.New databases and models increase the potential of computational drug designLiraglutide and other antidiabetics are strong candidates for repurposing to AD.Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studiesAlzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MTD design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

Ajmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s Disease

“…From the inception of amyloid cascade hypothesis to its reappraisal, it is considered to be the primary cause of this form of senile dementia [17,18]. With the advent of research and new disease progression insights, now we can assign more targets with responsibility towards either pathophysiology or associated symptoms [5]. Despite major pharma-research focused on discovering novel disease-modifying molecules, the current treatment for AD targets its affiliated symptoms only [6].…”

“…Despite advanced AD researches, the current treatment strategies for AD mainly deal with providing symptomatic relief by improving cholinergic neurotransmission in CNS. Currently approved drugs for AD includes anti-cholinesterase, such as donepezil, galanthamine, and NMDA (N-methyl-D-aspartate) antagonists (memantine) [5]. At present, no disease modifying drugs are available for the treatment of AD.…”

Development of coumarin–benzofuran hybrids as versatile multitargeted compounds for the treatment of Alzheimer’s Disease

“…To deal the several targets of AD simultaneously, we have proposed the dual‐acting multitargeted molecules as anti‐AD agents and accordingly developed the benzofuran (donepezil component known for AChE inhibition) and coumarin (known for the AChE inhibition antioxidant and anti‐Aβ self‐aggregation)‐based hybrids to provide new class of anti‐AD molecules as shown in Figure . The coupling of these two selected pharmacophores was designed through amidic linkage of aliphatic chain and adequate length of alkyl linker was optimized through molecular docking simulations, so that designed molecules can fit comfortably in the cavity of acetylcholinesterase ( Tc AChE) enzyme and provide maximum interaction with catalytic active site (CAS) and the peripheral anionic site (PAS) to induce maximum AChE inhibition.…”

Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

“…3, panel A) derived from the solution structure of Ab brils 16 (pdb id:2LMN) indicated that both the 8-chloroquinazoline and the pyrido [3,2] pyrimidine templates were oriented between C-and N-terminal region whereas the C4-phenethylamine substituent was closer to the turn region Asp23-Gly29 (distance $ 6-8Å). Hydrophobic interactions were the dominating force involved.…”