RATIONAL DESIGN OF ANTICONVULSANTS - A QUANTUM PHARMACOLOGICAL STUDY OF THE ION CHANNEL-MODULATING FMRFAMIDE TETRAPEPTIDE AS AN ENDOGENOUS ANTICONVULSANT

We applied the computational techniques of quantum pharmacology to exa mine molecular conformations (shapes and geometries) of the tetrapepti de FMR-Famide (L-Phe-L-Met-L-Arg-L-Phe-NH2), determining the geometric features necessary for anticonvulsant activity. The rigorous tiered h ierarchical approach used molecular mechanics, molecular dynamics, and semiempirical quantum mechanics calculational methods. Low-energy con formations showed pertinent conformational information to be considere d in the rational design of novel anticonvulsants. The FMRFamide pepti de 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 occup y the opposite face. The aromatic rings point away from each other alo ng the backbone, and this separation is consistent among the low-energ y conformations at similar to 11-12 Angstrom. The Met side chain inter acts with neither the peptide backbone nor the side chains of other re sidues. Molecular mechanics and semiempirical quantum mechanics calcul ations predict limited variation in the orientation of the Arg side ch ain.