Experimental and Theoretical Evaluation of the Ethynyl Moiety as a Halogen Bioisostere.

ABSTRACT: Bioisosteric replacements are widely used in medicinal chemistry to improve physicochemical and ADME properties of molecules while retaining or improving affinity. Here, using the p53 cancer mutant Y220C as a test case, we investigate both computationally and experimentally whether an ethynyl moiety is a suitable bioisostere to replace iodine in ligands that form halogen bonds with the protein backbone. This bioisosteric transformation is synthetically feasible via Sonogashira cross-coupling. In our test case of a particularly strong halogen bond, replacement of the iodine with an ethynyl group resulted in a 13-fold affinity loss. High-resolution crystal structures of the two analogues in complex with the p53-Y220C mutant enabled us to correlate the different affinities with particular fea

SUBMITTER: Wilcken R 

PROVIDER: S-EPMC4836799 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature