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Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β-Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

[ Vol. 16 , Issue. 7 ]

Author(s):

Richa Arya, Satya Prakash Gupta*, Sarvesh Paliwal, Swapnil Sharma, Kirtika Madan and Monika Chauhan   Pages 775 - 784 ( 10 )

Abstract:


Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals characterized by accumulated Amyloidal beta (A β) plaque in neurological areas. The βsecretase APP cleavage enzyme1 )BACE1 ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease

Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model.

Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated.

Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Keywords:

β-secretase APP cleavage enzyme-1, β-secretase, docking, fluorescence, micro plate, pharmacophore, virtual screening.

Affiliation:

Banasthali University, Banasthali-304022 (Raj.), Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut-250005, Banasthali University, Banasthali-304022 (Raj.), Banasthali University, Banasthali-304022 (Raj.), Banasthali University, Banasthali-304022 (Raj.), Banasthali University, Banasthali-304022 (Raj.)



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