Discovery of novel chemotypes for competitive AMPA receptor antagonists as potential antiepileptic agents through structure-based virtual screening of natural products library
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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.
KeywordsStructure-based screening AMPA receptor antagonists ROC Quantum mechanics Epilepsy Molecular dynamics
Authors are grateful to the Central University of Rajasthan for providing licensed Schrodinger molecular modeling software.
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.
- 9.Desos P, Lepagnol JM, Morain P, Lestage P, Cordi AA (1996) Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties. J Med Chem 39(1):197–206CrossRefGoogle Scholar
- 10.Canton T, Bohme GA, Boireau A, Bordier F, Mignani S, Jimonet P, Jahn G, Alavijeh M, Stygall J, Roberts S, Brealey C, Vuilhorgne M, Debono MW, Guern SL, Laville M, Briet D, Roux M, Stutzmann JM, Pratt J (2001) RPR 119990, a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J Pharmacol Exp Ther 299(1):314–322PubMedGoogle Scholar
- 11.Mignani S, Bohme GA, Birraux G, Boireau A, Jimonet P, Damour D, Genevois-Borella A, Debono MW, Pratt J, Vuilhorgne M, Wahl F, Stutzmann JM (2002) 9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): selective anticonvulsive and neuroprotective AMPA antagonist. Bioorg Med Chem 10(5):1627–1637CrossRefGoogle Scholar
- 13.Orain D, Ofner S, Koller M, Carcache DA, Froestl W, Allgeier H, Rasetti V, Nozulak J, Mattes H, Soldermann N, Floersheim P, Desrayaud S, Kallen J, Lingenhoehl K, Urwyler S (2012) 6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists. Bioorg Med Chem Lett 22(2):996–999CrossRefGoogle Scholar
- 14.Stutzmann JM, Bohme GA, Boireau A, Damour D, Debono MW, Genevois-Borella A, Imperato A, Jimonet P, Pratt J, Randle JCR, Ribeill Y, Vuilhorgne M, Mignani S (2000) 4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with in vivo activity. Bioorg Med Chem Lett 10(10):1133–1137CrossRefGoogle Scholar
- 15.Maestro, Version 10.4 (Epik Version 3.4; Impact Version 6.9; Prime Version 4.2, Glide Version 6.9; LigPrep, Version 3.6; QikProp, Version 4.6). (2015) Schrodinger, LLC, New YorkGoogle Scholar
- 16.Forge, Version, Cresset, Litlington, Cambridgeshire (UK) http://www.cresset-group.com/forge. Accessed 10 Dec. 2017
- 19.(2015) SciFinder™, Columbus (OH), American Chemical Society. https://scifinder.cas.org/scifinder/login. Accessed 10 Jan. 2018
- 23.Slon-Usakiewicz J, inventor; Waratah Pharmaceuticals Inc., assignee (2007) Screening methods for amyloid beta modulators. United States Patent US 2,007,134,449Google Scholar