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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

Binding modes of PK5176 (2, yellow carbons)and PK5211(3, green carbons) in complex with the p53-Y220C DNA-bindingdomain by X-ray crystallography. Both compounds share a nearly identicalbinding mode, with 3 shifted rigidly upward away fromLeu145 because of the increased length of its terminal ethynyl group.The I···O halogen bond between 2 and theprotein is shown as a purple broken line, and the CH···Ohydrogen bond between 3 and the protein is shown as alight green broken line.
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fig3: Binding modes of PK5176 (2, yellow carbons)and PK5211(3, green carbons) in complex with the p53-Y220C DNA-bindingdomain by X-ray crystallography. Both compounds share a nearly identicalbinding mode, with 3 shifted rigidly upward away fromLeu145 because of the increased length of its terminal ethynyl group.The I···O halogen bond between 2 and theprotein is shown as a purple broken line, and the CH···Ohydrogen bond between 3 and the protein is shown as alight green broken line.

Mentions: We determinedthe crystal structure of the p53-Y220C-3 complex at aresolution of 1.4 Å. The two acetylenic groups of the ligandfulfill two different roles: (i) the central ethynyl moiety providesa linear rigid linker and (ii) the terminal ethynyl substituent actsas a hydrogen bond donor and iodo bioisostere. Overall, the bindingmode is essentially the same as for the parent compound (2, Figure 3). The phenolmoiety binds to the center of the mutation-induced cavity, sandwichedbetween several prolines and a valine of loops S3/S4 and S7/S8. Thephenol hydroxyl forms a hydrogen bond with a structural water moleculeand an intramolecular hydrogen bond with the piperidine amino group.Via its acetylene linker, the ligand reaches into a different subsiteof the cavity where the benzamine moiety formed a CH···πinteraction with Pro153. As anticipated, the terminal acetylene groupforms a CH···O hydrogen bond with the main chain oxygenof Leu145 at the bottom of the largely hydrophobic central cavity,thus mimicking the halogen bond in 2. The distance betweenthe terminal carbon and the oxygen is 3.0 and 2.9 Å in chainsA and B, respectively, corresponding to a hydrogen bond of moderatestrength. As a result of the different distance between the donorand the closest carbon in the aromatic ring of the ligand (Csp2-Csp-Csp = 2.6 Å versus Csp2-I = 2.1 Å), 3 is slightly shifted as a rigid bodyby ∼0.5 Å along the longitudinal axis of the cavity comparedto 2, accompanied by similar small shifts of Pro153 and Pro222 in the flanking loops to accommodatethe ligand. The Csp-H···O angles in chainsA and B are 164.0° and 170.4°, respectively, a near-lineararrangement in accordance with that previously observed for the halogenbond formed by 2.


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)

Binding modes of PK5176 (2, yellow carbons)and PK5211(3, green carbons) in complex with the p53-Y220C DNA-bindingdomain by X-ray crystallography. Both compounds share a nearly identicalbinding mode, with 3 shifted rigidly upward away fromLeu145 because of the increased length of its terminal ethynyl group.The I···O halogen bond between 2 and theprotein is shown as a purple broken line, and the CH···Ohydrogen bond between 3 and the protein is shown as alight green broken line.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Binding modes of PK5176 (2, yellow carbons)and PK5211(3, green carbons) in complex with the p53-Y220C DNA-bindingdomain by X-ray crystallography. Both compounds share a nearly identicalbinding mode, with 3 shifted rigidly upward away fromLeu145 because of the increased length of its terminal ethynyl group.The I···O halogen bond between 2 and theprotein is shown as a purple broken line, and the CH···Ohydrogen bond between 3 and the protein is shown as alight green broken line.
Mentions: We determinedthe crystal structure of the p53-Y220C-3 complex at aresolution of 1.4 Å. The two acetylenic groups of the ligandfulfill two different roles: (i) the central ethynyl moiety providesa linear rigid linker and (ii) the terminal ethynyl substituent actsas a hydrogen bond donor and iodo bioisostere. Overall, the bindingmode is essentially the same as for the parent compound (2, Figure 3). The phenolmoiety binds to the center of the mutation-induced cavity, sandwichedbetween several prolines and a valine of loops S3/S4 and S7/S8. Thephenol hydroxyl forms a hydrogen bond with a structural water moleculeand an intramolecular hydrogen bond with the piperidine amino group.Via its acetylene linker, the ligand reaches into a different subsiteof the cavity where the benzamine moiety formed a CH···πinteraction with Pro153. As anticipated, the terminal acetylene groupforms a CH···O hydrogen bond with the main chain oxygenof Leu145 at the bottom of the largely hydrophobic central cavity,thus mimicking the halogen bond in 2. The distance betweenthe terminal carbon and the oxygen is 3.0 and 2.9 Å in chainsA and B, respectively, corresponding to a hydrogen bond of moderatestrength. As a result of the different distance between the donorand the closest carbon in the aromatic ring of the ligand (Csp2-Csp-Csp = 2.6 Å versus Csp2-I = 2.1 Å), 3 is slightly shifted as a rigid bodyby ∼0.5 Å along the longitudinal axis of the cavity comparedto 2, accompanied by similar small shifts of Pro153 and Pro222 in the flanking loops to accommodatethe ligand. The Csp-H···O angles in chainsA and B are 164.0° and 170.4°, respectively, a near-lineararrangement in accordance with that previously observed for the halogenbond formed by 2.

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