Twisted Amides Inferred from QSAR Analysis of Hydrophobicity and Electronic Effects on the Affinity of Fluoroaromatic Inhibitors of Carbonic Anhydrase

• Published in: Journal of organic chemistry Vol. 67; no. 2; pp. 582 - 584
• Main Authors: Madder, Ryan D, Kim, Chu-Young, Chandra, Pooja P, Doyon, Jeffrey B, Baird, Teaster A, Fierke, Carol A, Christianson, David W, Voet, Judith G, Jain, Ahamindra
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.01.2002
• Subjects: Amides - chemistry; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - metabolism; Chemical Phenomena; Chemistry, Physical; Combinatorial Chemistry Techniques; Drug Design; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Lyases; Magnetic Resonance Spectroscopy; Molecular Structure; Quantitative Structure-Activity Relationship; Sulfonamide; Enzyme; Ab initio method; Combinatorial chemistry; Enzyme inhibitor; Amides; Dissociation constant; Lyases; Hydrophobicity; Experimental study; Synthetic product; Structure activity relation; Chemical compound library; Carbonate dehydratase; Aromatic compound; Electronic effect; Fluorine Organic compounds; Carbon-oxygen lyases; Intramolecular interaction; Hydro-lyases
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0159385

QSAR has been used to elucidate the origin of the hydrophobicity and binding affinity of a small library of fluoroaromatic inhibitors of F131V carbonic anhydrase II. Our analysis predicted the presence of a twisted amide conformation for several bound inhibitors, which we confirmed crystallographically. We also determined that the hydrophobicity of the inhibitors as a whole results from the fragment hydrophobicities of their fluorobenzyl rings, corrected for field effects and the presence of an intramolecular F·H contact in solution. The loss of this interaction on binding to the enzyme makes the affinity sensitive to the same terms, but with the opposite dependence on the F·H contact. In the case of the four inhibitors bound as twisted amides, this F·H contact must be retained to some extent in the bound state in order for their affinities to be consistent with our QSAR analysis of the entire set of 17 molecules.