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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

Structural Formulas of the Three Compounds Used inThis WorkAffinities for p53-Y220C coredomain as measured by (direct) ITC are KD (PK5174) = 15.5 μM and KD (PK5176)= 20.6 μM.14 The affinity of PK5211(3) was determined indirectly as KD (PK5211) = 271 μM by competition ITC with PK5174 (1); see also Figure 2.
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sch1: Structural Formulas of the Three Compounds Used inThis WorkAffinities for p53-Y220C coredomain as measured by (direct) ITC are KD (PK5174) = 15.5 μM and KD (PK5176)= 20.6 μM.14 The affinity of PK5211(3) was determined indirectly as KD (PK5211) = 271 μM by competition ITC with PK5174 (1); see also Figure 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)

Structural Formulas of the Three Compounds Used inThis WorkAffinities for p53-Y220C coredomain as measured by (direct) ITC are KD (PK5174) = 15.5 μM and KD (PK5176)= 20.6 μM.14 The affinity of PK5211(3) was determined indirectly as KD (PK5211) = 271 μM by competition ITC with PK5174 (1); see also Figure 2.
© Copyright Policy
Related In: Results  -  Collection

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

sch1: Structural Formulas of the Three Compounds Used inThis WorkAffinities for p53-Y220C coredomain as measured by (direct) ITC are KD (PK5174) = 15.5 μM and KD (PK5176)= 20.6 μM.14 The affinity of PK5211(3) was determined indirectly as KD (PK5211) = 271 μM by competition ITC with PK5174 (1); see also Figure 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