Terpenoids as promising therapeutic molecules against Alzheimer’s disease: amyloid beta- and acetylcholinesterase-directed pharmacokinetic and molecular docking analyses

Alzheimer’s disease (AD) is a progressive neurological disorder of brain encompassing deterioration of cognitive functions and behavioural changes eventually leading to cell death and dementia. Several attempts have been made to treat AD by the use of combined drug therapy against acetylcholinesterase (AChE) and amyloid beta (Aβ) simultaneously with the aim to delay its progress. However, side effects of long-term administration of these drugs have directed research towards development of a new generation of therapeutics based on natural compounds. In this regard, one hundred terpenoids were analysed for their inhibitory potential against AChE and Aβ through molecular docking approach. The selected terpenoids were further screened for their pharmacokinetic properties, among which only 25 terpenoids were found to fulfil all the ADMET descriptors and drug likeness properties which are essential for ensuring the development of safer drugs. A triterpene, nimbolide, was found to be the most potent and safe inhibitor for both AChE and Aβ as compared to their respective drugs/known inhibitors. The results of docking were further confirmed using molecular dynamics simulation analysis of complexes of nimbolide with both the targets. Thus, the present work makes a foundation for further clinical investigations of nimbolide as a drug against AD.