RESUMO
Alzheimer's disease (AD), is characterized by a progressive loss of cognitive abilities as well as behavioral symptoms including disorientation, trouble solving problems, personality and mood changes. Acetylcholinesterase (AChE) is a promising target for symptomatic improvement in AD due to its consistent and early cholinergic deficit. This research has investigated the potential compounds from Catunaregam spinosa as AChE inhibitors as a treatment option for AD, aiming to enhance cholinergic neurotransmission and alleviate cognitive decline. Tacrine, the FDA's first approved treatment for AD, is no longer in use due to its hepatotoxicity. Box-Behnken design (BBD) modelling was used to optimise the ultrasonic extraction of alkaloids from the dried fruits of C. spinosa. GC-MS analysis revealed the presence of ninety phytoconstituents in the extract. Among them, eighty-nine new phytoconstituents are reported in this plant fruit for the first time. Out of ninety phytoconstituents, eight phytoconstituents showed the best binding affinity against the AChE enzyme, i.e., PDB IDs 1GQR, 1QTI and 4PQE of AD targets using iGEMDOCK. The lead hits were tested for their drug-like properties and atomistic binding mechanisms using in silico ADMET prediction, LigPlot analysis, and molecular dynamics simulation. The results suggest four compounds such as 1,4,7,10,13,16-hexaoxacyclooctadecane; butanoic acid, 3-methyl-2-[(phenylmethoxy)imino]-, trime; butane-1,2,3,4-tetraol; and D-(+)-ribonic acid.gamma-lactone as potent inhibitors of AChE for the possible treatment of AD.
RESUMO
Background: The current treatment of Alzheimer's disease (AD) is far from adequate. AD can be treated by inhibiting either ß-amyloid protein deposition or acetylcholinesterase enzyme activity. Many treatments for AD are directed at these 2 targets. In the present study, the phytoconstituents of Carissa carandas chloroform leaf extract were identified by gas chromatography-MS/MS analysis, and in silico molecular docking studies were performed to evaluate their potential against AD. Objectives: The present study aimed to identify the possible anti-Alzheimer's activity of novel phytoconstituents isolated from C carandas. Methods: The powdered leafy material was subjected to successive Soxhlet extraction using 3 different solvents: n-hexane, chloroform, and methanol. The chloroform extract was subjected to gas chromatography-MS/MS analysis, and the observed chromatogram revealed the presence of 48 chemical constituents. Among them, 42 new phytoconstituents are reported in this plant for the first time. The gas chromatography-MS/MS-identified phytoconstituents were evaluated by iGEMDOCK software against AD targets of ß-amyloid fibril (protein data bank ID: 2LMN) and recombinant human acetylcholinesterase (protein data bank ID: 3LII) ligands, and their anti-AD potential were compared with those of known inhibitors of galantamine and curcumin. Results: On the basis of results from both docking assays, the 5 compounds with the highest docking energy were further analyzed using in silico admetSAR web portal modeling for the evaluation of parameters such as intestinal absorption, blood-brain barrier permeation, carcinogenicity, and acute oral toxicity. Conclusions: The chloroform leaf extract of C carandas was found to contain constituents that have affinities for the 2 targets tested; that is, amyloid ß and acetylcholinesterase. The best docking scores were found for 7 compounds: 1-heneicosanol; N-nonadecanol-1; cholesta-4,6-dien-3-ol, (3beta); di-n-octyl phthalate; 7,9-di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione; 6-undecyl-5,6-dihydro-2H-pyran-2-one, and phenol, 2,4-di-t-butyl-6-nitro compounds, and these compounds were therefore suggested to be promising anti-AD lead compounds. Further, the target leads were subjected to ligplot analysis for their 2-dimensional representation of hydrogen bonding and hydrophobic interactions. Thus, the results obtained from the in silico study of C carandas leaf extract using these computational approaches indicate the presence of phytoconstituents that have affinities for the selected 2 targets of AD. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).
