Structure-based screening, ADMET profiling, and molecular dynamic studies on mGlu2 receptor for identification of newer antiepileptic agents

Abstract

Structure-based screening approach targeting mGlu2 receptor was carried out to identify good chemical starting points for anti-epileptic therapy. Interactive modes of final 12 compounds identified on the basis of screening of Asinex library, binding energy analysis, ADME profiling with special emphasis for CNS ranges, and toxicity analysis were studied and showed good binding modes in the mGluR2-active site. Enrichment studies for validating screening protocol were carried out which gave ROC values 0.98 (AUC = 0.96) for SP, 0.97 (AUC = 0.95) for XP with BEDROC analysis. Our results indicate that all the 12 hits showed good CNS drug-like properties, have better binding free energy and ADME profile as compared to co-crystallized ligand with the best ligand hit retaining conserved hydrogen bond interactions with Ala-166, Thr-168, Ser-145, and Arg-61 residues in bilobatevenus fly-trap domain of mGluR2 receptor. Molecular dynamics simulations proved that the two potential hits, qualifying all screening parameters, are stable in the receptor active site pocket, confirming the potential of the identified hits as a specific target for mGluR2. Because the newly discovered mGluR2 agonists are structurally different with T values ranging from 0.57 to 0.92, all of them can be considered for further de novo design methods.

Pharmacophore Modeling Guided by Conformational Dynamics Reveals Potent Anticancer Agents

“…Pharmacophore modeling in combination with virtual screening and molecular docking is a powerful strategy for discovery of novel compounds against a specific target. Many successful research have been put forth recently in this respect [26][27][28][29][30][31][32]. Ligand-based virtual screening methods enable fast screening based on a pharmacophore model that may be built upon a set of active ligands.…”