Abstract
Excerpt: 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, describeefforts to identify the common pharmacophore and to develop a ligand-receptor model for thebinding of these neurotoxins to site 5. Conformational analysis of brevetoxin A has been completedusing 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 calculatedrelative energies change, but no new minima appear. Like brevetoxin B, brevetoxin A has bothstraight and bent conformers available. Elimination of several G-ring crown conformers fromconsideration and comparison of the two brevetoxin backbones indicates that those that match mostclosely in overall shape and location of functional groups are straight. We postulate that the commonpharmacophore is a roughly cigar-shaped molecule (~30 A long) bound to its receptor primarily byhydrophobic and nonpolar solvation forces, possibly aided by strategically placed hydrogen bondsnear the site of the lactone carbonyl in the receptor.