| Abstract
| - QSAR has been used to elucidate the origin ofthe hydrophobicity and binding affinity of a small library offluoroaromatic inhibitors of F131V carbonic anhydrase II.Our analysis predicted the presence of a twisted amideconformation for several bound inhibitors, which we confirmed crystallographically. We also determined that thehydrophobicity of the inhibitors as a whole results from thefragment hydrophobicities of their fluorobenzyl rings, corrected for field effects and the presence of an intramolecularF·H contact in solution. The loss of this interaction onbinding to the enzyme makes the affinity sensitive to thesame terms, but with the opposite dependence on the F·Hcontact. In the case of the four inhibitors bound as twistedamides, this F·H contact must be retained to some extentin the bound state in order for their affinities to be consistentwith our QSAR analysis of the entire set of 17 molecules.
|
