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Discovery of novel chemotypes for competitive AMPA receptor antagonists as potential antiepileptic agents through structure-based virtual screening of natural products library

  • Pakhuri Mehta
  • Shubham Srivastava
  • Manish Sharma
  • Ruchi MalikEmail author
Original Research

Abstract

Competitive AMPA receptor antagonists serve as the promising and validated strategy towards the development of novel antiepileptic agents. For this purpose, the structure-based virtual screening approach on library of natural compounds led to the discovery of 11 novel diverse competitive AMPA receptor antagonists with better docking and dG bind scores than the co-crystallized ligand. Validation of the screening protocol was accomplished at three levels like superposition, enrichment, and simulation studies. Involvement of the crucial amino acid interactions such as Thr91 and Arg96 involved in the binding of the co-crystallized ligand was set as the basic criterion for selecting hits on the basis of the ligand–protein interactions. The topmost hit with best dG bind score was subjected to simulation studies, quantum mechanics, and hit optimization study. Computational models developed through validated virtual screening protocol with better pharmacokinetic performance provides in silico evidence towards the development of better therapeutic regime of epilepsy.

Keywords

Structure-based screening AMPA receptor antagonists ROC Quantum mechanics Epilepsy Molecular dynamics 

Notes

Acknowledgments

Authors are grateful to the Central University of Rajasthan for providing licensed Schrodinger molecular modeling software.

Funding

This study was funded by the Department of Science and Technology (INSPIRE fellowship Grant No. DST/INSPIRE/Fellowship/2014/241 and DST-Rajasthan Grant No. L7(3)S&T/R&D/2016/2616).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PharmacyCentral University of RajasthanAjmerIndia
  2. 2.School of PharmacyMaharishi Markandeshwar UniversityAmbalaIndia

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