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.
Highlights
A frequent task faced by medicinal chemists is to replace chemical moieties with known liabilities in a lead molecule
In our test case of a strong halogen bond, replacement of the iodine with an ethynyl group resulted in a 13-fold affinity loss
The chloro moiety in gefitinib is involved in a weak halogen bond[12] with the backbone carbonyl oxygen of Leu[788] in the back pocket of the ATP-binding site of the kinase,[18] and this contact is mimicked by the ethynyl group in the cocrystal structure of erlotinib[19] (Figure 1c)
Summary
0.003 au for chlorobenzene, bromobenzene, iodobenzene, and phenylacetylene. Color ranges of energies in atomic units are shown. The positive charge located at the protonated amine withdraws electron density from the halogen and ethynyl group and significantly increases the overall interaction energy for both systems This effect is further amplified by a reinforced intramolecular hydrogen bond between the protonated amine and the phenol oxygen, which in turn donates a weak hydrogen bond onto the negative electrostatic belt of either the iodine or the ethynyl π electron density (see Figures 1a and 4). This tuning effect is much stronger for the I···O halogen bond; here, the interaction energy ΔE at equilibrium distance is approximately −10 kcal/mol, whereas the C−H···O contact is “only” tuned to approximately −8.8 kcal/mol. Our QM studies indicate that the I···O halogen bond in the complex of 2 is favored compared with the “nonclassical hydrogen bond” in the complex of 3, most likely through a combination of its superior polarizability (tuning effect), its more suitable interaction geometry, and the better overall accommodation of the ligand within the binding pocket
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