Title

Molecular Docking and Pharmacological Investigations of Rivastigmine-Fluoxetine and Coumarin–Tacrine hybrids against Acetyl Choline Esterase

Authors

Affiliation

¹Research and Development Centre, Bharathiyar University, Coimbatore.641046, India; ²Malabar Christian College, Calicut, 673 001, India; ³Department of Bioinformatics, SIAS - Centre for Scientific Research, Safi Institute of Advanced Study Vazhayoor, Malappuram - 673633, Kerala, India.; ⁴Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore - 452010, India; ⁵School of Ocean Sciences and Technology, Kerala University of Fisheries and Ocean Studies, Panangad, Kochi 682506, India

Email

suresh.kufos@gmail.com; *Corresponding author

Article Type

Hypothesis

Date

Received July 15, 2015; Revised July 27, 2015; Accepted July 28, 2015; Published August 31, 2015

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. 

Keywords

Rivastigmine-Fluoxetine hybrids; Coumarin–Tacrine hybrids, Molecular docking, pharmacological profiling, Virtual screening.

Citation

Babitha et al. Bioinformation 11(8): 378-386 (2015)
 

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.