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Rational Design of Anticonvulsants: A Quantum Pharmacologic Study of the Ion Channel–Modulating FMRFamide Tetrapeptide as an Endogenous Anticonvulsant
Author(s) -
Dakin K. A.,
Weaver D. F.
Publication year - 1995
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1995.tb00492.x
Subject(s) - tetrapeptide , molecular mechanics , chemistry , molecular dynamics , bent molecular geometry , side chain , stereochemistry , peptide , computational chemistry , intramolecular force , organic chemistry , biochemistry , polymer
Summary: 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‐NH 2 ), 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 ∼11–12 Å. The Met side chain interacts with neither the peptide back bone 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.