Rational Design of Anticonvulsants: A Quantum Pharmacologic Study of the Ion Channel–Modulating FMRFamide Tetrapeptide as an Endogenous Anticonvulsant

Abstract

We applied the computational techniques of quantum pharmacology to examine molecular conformations (shapes and geometries) of the tetrapeptide FMR-Famide (L-Phe-L-Met-L-Arg-L-Phe-NH2), determining the geometric features necessary for anticonvulsant activity. The rigorous tiered hierarchical approach used molecular mechanics, molecular dynamics, and semiempirical quantum mechanics calculational methods. Low-energy conformations showed pertinent conformational information to be considered in the rational design of novel anticonvulsants. The FMRFamide peptide backbone assumes a bent but primary planar geometry. Distinct polar and nonpolar regions are created as the two Phe residues occupy one "face" of the bent conformation, while the Met and Arg residues occupy the opposite face. The aromatic rings point away from each other along the backbone, and this separation is consistent among the low-energy conformations at approximately 11-12 A. The Met side chain interacts with neither the peptide backbone nor the side chains of other residues. Molecular mechanics and semiempirical quantum mechanics calculations predict limited variation in the orientation of the Arg side chain.