Alzheimer’s Disease Therapy: Present and Future Molecules

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and a cause of progressive dementia worldwide. It is generally attributed to multiple genetic factors and, thus, is genetically heterogeneous. The two basic pathological features of AD are extra-neuronal plaques of misfolded β-amyloid proteins and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. On therapeutic front, presently there are only two targets for AD, namely, acetylcholinesterase inhibitors and NMDA receptor antagonists that improve the cognitive functions. But these drugs do not act in ameliorating the pathological causes behind AD. Therefore, active research is the need of the hour toward AD treatment. In designing novel drugs or modifying existing molecules, computational approaches have proved to be very useful in saving time and money. Virtual screening, modeling, and docking are being widely used for the last few years by researchers globally. These have indeed helped with a lot of promising compounds on the desk. With continuous efforts in bringing down the problem of AD, researchers have targeted some widely known neuronal targets such as muscarinic/nicotinic acetylcholine receptors, tau hyperphosphorylation, beta-secretase enzyme, and β-amyloid plaques, while many new targets such as sigma-1, α-secretase, histamine H3 receptor, and Lingo-1 have been identified and molecules targeting them are being developed. Apart from synthesizing chemical entities, several natural compounds have been extracted and tested for AD. Compounds such as flavonoids, curcumin, alkaloids, and terpenoids have shown promising activity against various targets. Thus, owing to the helpful hand of computational biology and natural treasures, several promising molecules are on the front, and many candidates are in different clinical trial phases that give positive hopes in near future.