Year : 2013 | Volume
: 2 | Issue : 3 | Page : 139--150
Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations
A Mobeen, D Pradhan, V Priyadarshini, M Munikumar, S Sandeep, A Umamaheswari
Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
Background: Alzheimer's disease (AD) is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP) by β-secretase generates peptide fragment Aβ42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of β-secretase results in accumulation of insoluble form of Aβ peptides (senile plaques) representing the protein as an attractive drug target of AD. Methods: Five recently reported β-secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid) structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of β-secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS)-2005 force field. Structure based virtual screening was performed for β-secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore.
Results: Eight lead molecules were identified to have better binding affinity (lower XP Gscore) compared to five existing β-secretase antagonists and appear to have good pharmacological properties. Binding orientations of the lead molecules were in well agreement with existing inhibitors. Lead1 showed lowest XP Gscore (-10.72 Kcal/mol). Molecular dynamics (MD) simulations of β-secretase-lead1 complex was stable in all trajectories.
Conclusion: Lead1 is proposed as potent inhibitor of β-secretase and thus could be considered for rational drug design against AD.
Associate Professor & Co-ordinator of BIF, Department of Bioinformatics, SVIMS Bioinformatics Centre, Sri Venkateswara Institute of Medical Sciences, Tirupati
|How to cite this article:|
Mobeen A, Pradhan D, Priyadarshini V, Munikumar M, Sandeep S, Umamaheswari A. Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations.J Clin Sci Res 2013;2:139-150
|How to cite this URL:|
Mobeen A, Pradhan D, Priyadarshini V, Munikumar M, Sandeep S, Umamaheswari A. Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations. J Clin Sci Res [serial online] 2013 [cited 2020 Apr 10 ];2:139-150
Available from: http://www.jcsr.co.in/article.asp?issn=2277-5706;year=2013;volume=2;issue=3;spage=139;epage=150;aulast=Mobeen;type=0