title: Molecular Docking and Pharmacological Investigations of Rivastigmine-Fluoxetine and Coumarin-Tacrine hybrids against Acetyl Choline Esterase.
abstract: The present AChE inhibitors have been successful in the treatment of Alzheimer׳s Diseases however suffers serious side effects. Therefore in this view, the present study was sought to identify compounds with appreciable pharmacological profile targeting AChE. Analogue of Rivastigmine and Fluoxetine hybrid synthesized by Toda et al, 2003 (dataset1), and Coumarin-Tacrine hybrids synthesized by Qi Sun et al (dataset2) formed the test compounds for the present pharmacological evaluation. p-cholorophenyl substituted Rivastigmine and Fluoxetine hybrid compound (26d) from dataset 1 and -OCH3 substitute Coumarin-Tacrine hybrids (1h) from dataset 2 demonstrated superior pharmacological profile. 26 d showed superior pharmacological profile comparison to the entire compounds in either dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify still better compound with pharmacological profile than 26 d and 1h, virtual screening was performed. The best docked compound (PubCId: PubCid: 68874404) showed better affinity than its parent 26 d, however showed poor ADME profile and AMES toxicity. CHEMBL2391475 (PubCid: 71699632) similar to 1h had reduced affinity in comparison to its parent compound 1h. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report p-cholorophenyl substituted rivastigmine and fluoxetine hybrid (26d) to be a potential candidate for AcHE inhibition which in addition can overcome narrow therapeutic window of present AChE inhibitors in clinical treatment of Alzheimer׳s disease.
  
  
  BACKGROUND
  AD - Alzheimer׳s Disease, AChE - Acetyl Choline Estarase, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank.
authors.affiliation: Research and Development Centre, Bharathiyar University, Coimbatore.641046, India ; Malabar Christian College, Calicut, 673001, India.
authors.forename: Pallikkara Pulikkal
authors.initials: PP
authors.lastname: Babitha
authors.affiliation: Department of Bioinformatics, SIAS - Centre for Scientific Research, Safi Institute of Advanced Study Vazhayoor,Malappuram - 673633, Kerala, India.
authors.forename: Mohammed Marunnan
authors.initials: MM
authors.lastname: Sahila
authors.affiliation: Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore - 452010, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.affiliation: Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore - 452010, India.
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.affiliation: Research and Development Centre, Bharathiyar University, Coimbatore.641046, India ; School of Ocean Sciences and Technology, Kerala University of Fisheries and Ocean Studies, Panangad, Kochi 682506, India.
authors.forename: Sivanpillai
authors.initials: S
authors.lastname: Sureshkumar
keywords: Coumarin–Tacrine hybrids; Molecular docking; Rivastigmine-Fluoxetine hybrids; Virtual screening; pharmacological profiling