Computational approaches have been helpful in high throughput screening of drug libraries and designing ligands against receptors. Alzheimer's disease is a complex neurological disorder, which causes dementia. In this disease neurons are damaged due to formation of Amyloid-beta plaques and neurofibrillary tangles, which along with some other factors contributes to disease development and progression. The objective of this study was to predict tertiary structures of five G-protein coulped neurotransmitter receptors; CHRM5, CYSLTR2, DRD5, GALR1 and HTR2C, that are upregulated in Alzheimer's disease, and to screen potential inhibitors for against these receptors. In this study, Comparative modelling, molecular docking, MMGBSA analysis, ADMET screening and molecular dynamics simulation were performed. Tertiary structures of the five GPCRs were predicted and further subjected to molecular docking against natural compounds. Pharmacokinetic studies of natural compounds were also conducted for assessing drug-likeness properties. Molecular dynamics simulations were performed to investigate the structural stability and binding affinities of each complex. Finally, the results suggested that ZINC04098704, ZINC31170017, ZINC05998597, ZINC67911229, and ZINC67910690 had better binding affinity with CHRM5, CYSLTR2, DRD5, GALR1, and HTR2C (5-HT2C) proteins, respectively.Communicated by Ramaswamy H. Sarma.
Keywords: Alzheimer's disease; MD simulation; inhibitors; molecular docking; screening; tertiary structure.