• Users Online: 153
  • Print this page
  • Email this page
ORIGINAL ARTICLE
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


Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Correspondence Address:
A Umamaheswari
Associate Professor & Co-ordinator of BIF, Department of Bioinformatics, SVIMS Bioinformatics Centre, Sri Venkateswara Institute of Medical Sciences, Tirupati
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


Rights and PermissionsRights and Permissions

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.


[PDF]*
Print this article     Email this article
 Next article
 Previous article
 Table of Contents

 Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
 Citation Manager
 Access Statistics
 Reader Comments
 Email Alert *
 Add to My List *
 * Requires registration (Free)
 

 Article Access Statistics
    Viewed22    
    Printed3    
    Emailed0    
    PDF Downloaded13    
    Comments [Add]    

Recommend this journal