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

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.

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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).

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Correspondence to Ruchi Malik.

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Mehta, P., Srivastava, S., Sharma, M. et al. Discovery of novel chemotypes for competitive AMPA receptor antagonists as potential antiepileptic agents through structure-based virtual screening of natural products library. Struct Chem 30, 1159–1172 (2019). https://doi.org/10.1007/s11224-018-1269-z

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Keywords

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