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

The marine neurotoxins brevetoxin A, brevetoxin B, and ciguatoxin bind to the same site (site 5) on the voltage-gated sodium channel. This w ork, and the following paper in this issue, describe efforts to identi fy the common pharmacophore and to develop a ligand-receptor model for the binding of these neurotoxins to site 5. Conformational analysis o f brevetoxin A has been completed using ah internal coordinate Monte C arlo search protocol. Within 6 kcal/mol of the global minimum (in vacu o), there are 48 conformations of brevetoxin A. In chloroform or water solvent, the calculated relative energies change, but no new minima a ppear. Like brevetoxin B, brevetoxin A has both straight and bent conf ormers 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 f unctional groups are straight. We postulate that the common pharmacoph ore is a roughly cigar-shaped molecule (similar to 30 Angstrom long) b ound to its receptor primarily by hydrophobic and nonpolar solvation f orces, possibly aided by strategically placed,hydrogen bonds near the site of the lactone carbonyl in the receptor.