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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

Distance scans of ligandsderived from PK5176 (2)and PK5211 (3) with N-methylacetamide.(a) Ligand and carbonyl oxygen model systems used for the distancescans. (b) Distance scan plots for the four ligand models with N-methylacetamide. Labels next to the plotted curves denotewhether the starting geometries were derived from chain A or B ofthe respective crystal structures. Black dots indicate the bond distanceobserved in the crystal structure.
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fig5: Distance scans of ligandsderived from PK5176 (2)and PK5211 (3) with N-methylacetamide.(a) Ligand and carbonyl oxygen model systems used for the distancescans. (b) Distance scan plots for the four ligand models with N-methylacetamide. Labels next to the plotted curves denotewhether the starting geometries were derived from chain A or B ofthe respective crystal structures. Black dots indicate the bond distanceobserved in the crystal structure.

Mentions: To understand better the differencesin interaction strength, we focused on the key interaction betweenthe ligand and the carbonyl oxygen of Leu145 (halogen bond vs CH···Ohydrogen bond). In our distance scans, Leu145 was represented as N-methylacetamide. For the ligands, we chose two model systemsof different sizes and properties, representing substructures of theoriginal ligands in their physiological protonation states: (i) 2-iodo-4,6-dimethylphenolor 2-ethynyl-4,6-dimethylphenol as “capped methyl”,the smallest substituted and uncharged fragments, and (ii) 1-(5-ethynyl-2-hydroxy-3-iodophenyl)-N,N-dimethylmethanaminium or 1-(3,5-diethynyl-2-hydroxyphenyl)-N,N-dimethylmethanaminium as “cappedamine”, the more realistic, positively charged model systemsincluding the protonated amine side chain (Figure 5a). Comparison of (i) and (ii) provides informationon the tuning effects of the protonated amine on the interaction withthe carbonyl oxygen. We have used this approach and similar modelsystems to systematically characterize halogen bonds with variousinteraction partners in recent years.27,29,30 All interaction geometries were extracted from chainsA and B of the respective crystal structures of the complexes formedby 2 (4AGP) and 3 (5A7B). Hydrogen atoms were added to the model systems andoptimized using the MP2/def2-TZVPP level of theory. Coordinates ofheavy atoms were kept frozen. Starting from the optimized geometries,the distance between ligand and carbonyl oxygen was changed in stepsof 0.1 Å, and interaction energies were calculated. Figure 5b shows interactionenergies as a function of the distance between the iodo- or ethynyl-substitutedaromatic carbon atom of the scaffold and the carbonyl oxygen.


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)

Distance scans of ligandsderived from PK5176 (2)and PK5211 (3) with N-methylacetamide.(a) Ligand and carbonyl oxygen model systems used for the distancescans. (b) Distance scan plots for the four ligand models with N-methylacetamide. Labels next to the plotted curves denotewhether the starting geometries were derived from chain A or B ofthe respective crystal structures. Black dots indicate the bond distanceobserved in the crystal structure.
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fig5: Distance scans of ligandsderived from PK5176 (2)and PK5211 (3) with N-methylacetamide.(a) Ligand and carbonyl oxygen model systems used for the distancescans. (b) Distance scan plots for the four ligand models with N-methylacetamide. Labels next to the plotted curves denotewhether the starting geometries were derived from chain A or B ofthe respective crystal structures. Black dots indicate the bond distanceobserved in the crystal structure.
Mentions: To understand better the differencesin interaction strength, we focused on the key interaction betweenthe ligand and the carbonyl oxygen of Leu145 (halogen bond vs CH···Ohydrogen bond). In our distance scans, Leu145 was represented as N-methylacetamide. For the ligands, we chose two model systemsof different sizes and properties, representing substructures of theoriginal ligands in their physiological protonation states: (i) 2-iodo-4,6-dimethylphenolor 2-ethynyl-4,6-dimethylphenol as “capped methyl”,the smallest substituted and uncharged fragments, and (ii) 1-(5-ethynyl-2-hydroxy-3-iodophenyl)-N,N-dimethylmethanaminium or 1-(3,5-diethynyl-2-hydroxyphenyl)-N,N-dimethylmethanaminium as “cappedamine”, the more realistic, positively charged model systemsincluding the protonated amine side chain (Figure 5a). Comparison of (i) and (ii) provides informationon the tuning effects of the protonated amine on the interaction withthe carbonyl oxygen. We have used this approach and similar modelsystems to systematically characterize halogen bonds with variousinteraction partners in recent years.27,29,30 All interaction geometries were extracted from chainsA and B of the respective crystal structures of the complexes formedby 2 (4AGP) and 3 (5A7B). Hydrogen atoms were added to the model systems andoptimized using the MP2/def2-TZVPP level of theory. Coordinates ofheavy atoms were kept frozen. Starting from the optimized geometries,the distance between ligand and carbonyl oxygen was changed in stepsof 0.1 Å, and interaction energies were calculated. Figure 5b shows interactionenergies as a function of the distance between the iodo- or ethynyl-substitutedaromatic carbon atom of the scaffold and the carbonyl oxygen.

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