Rational Design of Diflunisal Analogues with Reduced Affinity for Human Serum Albumin

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• 作者：Hongyuan Mao ; Philip J. Hajduk ; Richard Craig ; Randy Bell ; Tony Borre ; and Stephen W. Fesik
• 刊名：Journal of the American Chemical Society
• 出版年：2001
• 出版时间：October 31, 2001
• 年：2001
• 卷：123
• 期：43
• 页码：10429 - 10435
• 全文大小：474K
• 年卷期：v.123,no.43(October 31, 2001)
• ISSN：1520-5126

文摘

Many lead compounds bind to serum albumin and exhibit markedly reduced efficacy in vivo ascompared to their potency in vitro. To aid in the design of compounds with reduced albumin binding, weperformed nuclear magnetic resonance (NMR) structural and binding studies on the complex between domainIII of human serum albumin (HSA-III) and diflunisal, a cyclooxygenase inhibitor with antiinflammatory activity.The structural studies indicate that the aromatic rings of diflunisal are involved in extensive and specificinteractions with hydrophobic residues that comprise the binding pocket in subdomain IIIA. The carboxylicacid of diflunisal forms electrostatic interactions with the protein similar to those observed in the X-ray structureof HSA complexed to myristic acid. In addition to the structural studies, NMR-derived binding constants wereobtained for diflunisal and closely related analogues to develop a structure-affinity relationship for binding tosubdomain IIIA. On the basis of the structural and binding data, compounds were synthesized that exhibitmore than a 100-fold reduction in binding to domain III of HSA, and nearly a 10-fold reduction in affinity forfull length albumin. Significantly, several of these compounds maintain activity against cyclooxygenase-2.These results suggest a rational strategy for designing out albumin binding in potential drug molecules byusing structure-based design in conjunction with NMR-based screening.