Crystal structure of 1-(E)- [(5‑bromo-2-hydroxybenzylidene amino) pyrrolidin-2-one]: Design, synthesis and computational evaluation of a novel racetam congener for epilepsy

Abstract

The present investigation illustrates the conceptualization, synthesis, crystallographic analysis, and computational assessment of a new racetam derivative with a pyrrolidone ring as the pharmacophore. The compound demonstrates drug-like characteristics similar to LEV, an approved anti-epileptic drug, indicating its potential for developing novel epilepsy drugs. Molecular docking and molecular dynamic simulations were used to evaluate the binding affinity between the compound and SV2A, a protein-ligand complex. The protein-ligand complex attained structural equilibrium in the final 50 nanoseconds of the 200 nanosecond molecular dynamics simulation. The analysis reveals that regions with higher flexibility are primarily located in the extramembrane regions of the protein. Intermolecular contact analysis reveals hydrogen bonding and hydrophobic interactions as the primary types of interactions. The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation highlights the energetic aspects of ligand binding and the participation of important residues in the binding pocket. Unique interactions like those involving bifurcated hydrogen bonding, and novel pi-anion interaction makes the study significant. Quantum chemical calculations for the compound (LIG) done using DFT corroborates the protein-ligand interactions on the basis of Molecular Electrostatic Potential (MEP) maps. The study establishes the structure-activity relationship (SAR) of the newly developed pyrrolidone-based compound, identifying it as a promising lead molecule for epilepsy treatment.