Conformational Analysis of the Sodium Channel Modulator, Brevetoxin A, Comparison with Brevetoxin B Conformations, and a Hypothesis about the Common Pharmacophore of the “Site 5” Toxins

Abstract

The marine neurotoxins brevetoxin A, brevetoxin B, and ciguatoxin bind to the same site (site 5) on the voltage-gated sodium channel. This work, and the following paper in this issue, describe efforts to identify the common pharmacophore and to develop a ligand-receptor model for the binding of these neurotoxins to site 5. Conformational analysis of brevetoxin A has been completed using an internal coordinate Monte Carlo search protocol. Within 6 kcal/mol Of the global minimum (in vacuo), there are 48 conformations of brevetoxin A. In chloroform or water solvent, the calculated relative energies change, but no new minima appear. Like brevetoxin B, brevetoxin A has both straight and bent conformers available. Elimination of several G-ring crown conformers from consideration and comparison of the two brevetoxin backbones indicates that those that match most closely in overall shape and location of functional groups are straight. We postulate that the common pharmacophore is a roughly cigar-shaped molecule (~30 Å long) bound to its receptor primarily by hydrophobic and nonpolar solvation forces, possibly aided by strategically placed hydrogen bonds near the site of the lactone carbonyl in the receptor. © 1994, American Chemical Society. All rights reserved.