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

Wilcken R, Zimmermann MO, Bauer MR, Rutherford TJ, Fersht AR, Joerger AC, Boeckler FM - ACS Chem. Biol. (2015)

Bottom Line: This bioisosteric transformation is synthetically feasible via Sonogashira cross-coupling.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

Potential for bioisosterism between ethynyl and halogen substituents.(a) Electrostatic potentials plotted onto the isodensity surfacesat 0.003 au for chlorobenzene, bromobenzene, iodobenzene, and phenylacetylene.Color ranges of energies in atomic units are also shown. Calculationswere done at the MP2/TZVPP level of theory. (b) Structural formulasfor gefitinib (left) and erlotinib (right) with the chlorine-to-ethynylsubstitution highlighted. (c) Cocrystal structure of gefitinib boundto EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry ofthe Cl···O halogen bond is highlighted in yellow.
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fig1: Potential for bioisosterism between ethynyl and halogen substituents.(a) Electrostatic potentials plotted onto the isodensity surfacesat 0.003 au for chlorobenzene, bromobenzene, iodobenzene, and phenylacetylene.Color ranges of energies in atomic units are also shown. Calculationswere done at the MP2/TZVPP level of theory. (b) Structural formulasfor gefitinib (left) and erlotinib (right) with the chlorine-to-ethynylsubstitution highlighted. (c) Cocrystal structure of gefitinib boundto EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry ofthe Cl···O halogen bond is highlighted in yellow.

Mentions: The ethynyl (or “acetylene CH”) group is an interestingexample of a nonclassical bioisostere because of its versatility:its π cloud is useful for mimicking aromatic systems,3,4 and its polarized −CH moiety is a weak hydrogen bond donorand is a replacement for an iodine atom in a study on p53-HDM2 inhibitors.5,6 The molecular electrostatic potentials for halobenzenes (Cl, Br,I) and phenylacetylene are remarkably similar, both bearing an areaof positive charge at the tip of the C-X/H bond (where X = Cl, Br,I, or ethynyl) as well as an area of negative charge perpendicularto the C-X/H bond (Figure 1a). The paradigm of halogen bonding, which is based on thisanisotropic electron density distribution (the σ-hole7,8), has attracted attention in life sciences9−11 and drug discovery.12−16


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

Wilcken R, Zimmermann MO, Bauer MR, Rutherford TJ, Fersht AR, Joerger AC, Boeckler FM - ACS Chem. Biol. (2015)

Potential for bioisosterism between ethynyl and halogen substituents.(a) Electrostatic potentials plotted onto the isodensity surfacesat 0.003 au for chlorobenzene, bromobenzene, iodobenzene, and phenylacetylene.Color ranges of energies in atomic units are also shown. Calculationswere done at the MP2/TZVPP level of theory. (b) Structural formulasfor gefitinib (left) and erlotinib (right) with the chlorine-to-ethynylsubstitution highlighted. (c) Cocrystal structure of gefitinib boundto EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry ofthe Cl···O halogen bond is highlighted in yellow.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4836799&req=5

fig1: Potential for bioisosterism between ethynyl and halogen substituents.(a) Electrostatic potentials plotted onto the isodensity surfacesat 0.003 au for chlorobenzene, bromobenzene, iodobenzene, and phenylacetylene.Color ranges of energies in atomic units are also shown. Calculationswere done at the MP2/TZVPP level of theory. (b) Structural formulasfor gefitinib (left) and erlotinib (right) with the chlorine-to-ethynylsubstitution highlighted. (c) Cocrystal structure of gefitinib boundto EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry ofthe Cl···O halogen bond is highlighted in yellow.
Mentions: The ethynyl (or “acetylene CH”) group is an interestingexample of a nonclassical bioisostere because of its versatility:its π cloud is useful for mimicking aromatic systems,3,4 and its polarized −CH moiety is a weak hydrogen bond donorand is a replacement for an iodine atom in a study on p53-HDM2 inhibitors.5,6 The molecular electrostatic potentials for halobenzenes (Cl, Br,I) and phenylacetylene are remarkably similar, both bearing an areaof positive charge at the tip of the C-X/H bond (where X = Cl, Br,I, or ethynyl) as well as an area of negative charge perpendicularto the C-X/H bond (Figure 1a). The paradigm of halogen bonding, which is based on thisanisotropic electron density distribution (the σ-hole7,8), has attracted attention in life sciences9−11 and drug discovery.12−16

Bottom Line: This bioisosteric transformation is synthetically feasible via Sonogashira cross-coupling.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus