title: Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), β-secretase (BACE-1), and amyloid β (Aβ) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment.
authors.affiliation: Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Sneha B
authors.initials: SB
authors.lastname: Bansode
authors.affiliation: Physical Chemistry Division, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Asis K
authors.initials: AK
authors.lastname: Jana
authors.affiliation: Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Kedar B
authors.initials: KB
authors.lastname: Batkulwar
authors.affiliation: Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Shrikant D
authors.initials: SD
authors.lastname: Warkad
authors.affiliation: Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Rakesh S
authors.initials: RS
authors.lastname: Joshi
authors.affiliation: Physical Chemistry Division, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Sengupta
authors.affiliation: Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Mahesh J
authors.initials: MJ
authors.lastname: Kulkarni
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D007700:Kinetics; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D011530:Protriptyline / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000928:Antidepressive Agents; D008024:Ligands; D011530:Protriptyline; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases