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

DOI: 10.1021/acschembio.5b00515 DOI Help
PMID: 26378745 PMID Help

Authors: Rainer Wilcken (MRC Centre) , Markus O. Zimmermann (Eberhard Karls Universität Tübingen) , Matthias R. Bauer (MRC Laboratory of Molecular Biology) , Trevor J. Rutherford (MRC Laboratory of Molecular Biology) , Alan R. Fersht (MRC Laboratory of Molecular Biology) , Andreas Christian Joerger (Centre for Protein Engineering, Medical Research Council) , Frank Boeckler (Eberhard Karls Universität Tübingen)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 10 (12)

State: Published (Approved)
Published: October 2015

Open Access Open Access

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 features of the binding site and subtle changes in ligand binding mode. In addition, using QM calculations and analyzing the PDB, we provide general guidelines for identifying cases where such a transformation is likely to improve ligand recognition.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 20/11/2015 14:38

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