Structure-Based Drug Design: Progress Toward the Discovery of the Elusive Bradykinin Receptor Antagonists

Abstract

The de nova design of a non-peptide bradykinin receptor antagonist (or the optimization of a lead discovered by random screening) will ultimately require knowledge about the receptor topology. In the absence of an experientally-determined structure of the bradykinin-bradykinin receptor complex, we have attempted to gain insights from other sources. Specifically, we have synthesized conformationally constrained lignads, and completed extensive computer modeling and mutagenesis experiments on the bradykinin receptor. For the former, the recently reported hydroxyproline ether­ containing peptides have been useful in mapping the bradykinin receptor topology. Moreover, using systematic synthetic modifications, we have explored the relative importances of selected amide bonds 1 and side chains in second generation peptides and have made a series of and/or N-methyl 1 substitutions at positions four and five which led to the discovery of two new cyclic peptide antagonists. 1 For the latter, computational simulations led to a proposed model of bradykinin bound to its receptor which was found to be in good agreement with mutagens is results. This model led ultimately to the design and synthesis of D-Arg0-Arg 1 -(12- aminododecanoy1)2-Ser3-D-Tic4-0ic5-Arg6, a pseudo-peptide leading into a third generation of antagonists. Further improvements in tis lead structure were achieved via combinatorial non-peptide libraries.