Crucial effect of hydration in a model for the antiepileptic vigabatrin and the prosthetic group interaction

Abstract

The feasibility of a model for the first step of the interaction between the antiepileptic VGB (γ-vinyl GABA) and the prosthetic group PLP (pyridoxal phosphate) is studied. In this model, C_γH in VGB is oriented towards the center of the PLP ring prior to a Schiff base formation between them. Hydration is mimicked through first molecular mechanics and then molecular dynamics, both with the Amber force field. The first hydration shell of six water molecules is shown to play a crucial role. Hydrogen bonds are formed between them and (a) the carboxyl VGB group and (b) the phosphate PLP group. The corresponding 3-center MO bond indices have, accordingly, significant values.