title: Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer's plaque pathology.
abstract: Alzheimer's is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37-43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer's disease.
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Jaspreet Kaur
authors.initials: JK
authors.lastname: Dhanjal
authors.affiliation: Apaji Institute of Mathematics & Applied Computer Technology, Banasthali University, Tonk 304022, Rajasthan, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Biotechnology, Delhi Technological University, New Delhi 110042, India.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, University of Kashmir, Srinagar 190006, India.
authors.forename: Rabia
authors.initials: R
authors.lastname: Hamid
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: abhinavgr@gmail.com.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008024:Ligands; D056004:Molecular Dynamics Simulation; D058225:Plaque, Amyloid / Q000201:enzymology* / Q000473:pathology*; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D008024:Ligands; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s; BACE-1; Docking; High throughput virtual screening; Molecular dynamics simulation; Natural compound