title: Identification of abelson tyrosine kinase inhibitors as potential therapeutics for Alzheimer's disease using multiple e-pharmacophore modeling and molecular dynamics.
abstract: Efforts to combat Alzheimer's disease are focused predominantly on inhibiting the activity of the enzyme(s) that have been identified to be responsible for the production of the amyloid-forming peptide. However, the inherent complexity associated with the network of pathways leading to the disease may involve additional targets for designing effective therapies. Recent experimental findings have identified abelson tyrosine kinase, a non-receptor kinase as a new target for Alzheimer's. In this work, we employed energy optimized multiple pharmacophore modeling strategy from multiple c-Abl structures bound with ligands in the inactive ATP binding conformation (DFG-out). Virtual screening followed by docking of molecules from ChemBridge resulted in the identification of 10 best scoring molecules. MD simulations of the top three complexes revealed that Compound A, C are the most stable complexes with the most persistent protein-ligand interactions consistent with the calculated binding affinities for the top three compounds. Given the implied role of c-Abl not only in AD but in Parkinson's disease, the identified compounds may serve as leads for effective neurotherapeutics.
authors.affiliation: a Department of Biological Sciences , Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Jawaharnagar, Hyderabad 500078 , Telangana , India.
authors.forename: Ravichand
authors.initials: R
authors.lastname: Palakurti
authors.affiliation: a Department of Biological Sciences , Birla Institute of Technology & Science-Pilani , Hyderabad Campus, Jawaharnagar, Hyderabad 500078 , Telangana , India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Vadrevu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D016315:Proto-Oncogene Proteins c-abl
keywords: Alzheimer’s disease; MM-GBSA; abelson tyrosine kinase; blood-brain barrier; docking; e-pharmacophore; molecular dynamics; virtual screening