title: Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking.
abstract: Alzheimer's (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression. β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD.
authors.affiliation: Apaji Institute of Mathematics & Applied Computer Technology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Goyal
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, Rajasthan 304022, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Chetna
authors.initials: C
authors.lastname: Tyagi
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.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D004095:Dihydropyridines / Q000737:chemistry* / Q000627:therapeutic use; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004095:Dihydropyridines; D058851:GPI-Linked Proteins; C038806:1,4-dihydropyridine; C548244:ACHE protein, human; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human