Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel

Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is wide ly used to correlate biological activity with observed differences in steri c and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structurally diverse 5-phenylhydantoin analogues, to delineate structural and electrostatic features important for enhanced sodi um channel binding. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as log IC50) and the Co MFA descriptor column generated a final non-cross-validated model with R-2 = 0.988 for the training set. The final CoMFA model explained the data bett er than a simpler correlation with log P (R-2 = 0.801) for the same trainin g set. The CoMFA steric and electrostatic maps described two general featur es that result in enhanced binding to the sodium channel. These include a p referred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. This model was then utilized to accurately predict literature sodium channel activities for hydantoins 14-20, which were not included in the training set. Finally the hydantoin CoMFA model was used to design the structurally novel alpha-hydroxy-alpha-phenylamide 21. Synthesi s and subsequent sodium channel evaluation of compound 21 (predicted IC50 = 9 mu M, actual IC50 = 9 mu M), a good binder to the sodium channel, establ ished that the intact hydantion ring is not necessary for efficient binding to this site. Thus alpha-hydroxy-alpha-phenylamides may represent a new cl ass of ligands that bind with increased potency to the sodium channel.