Diamondoid Amino Acid‐Based Peptide Kinase A Inhibitor Analogues

• Published in: ChemMedChem 2019-03, Vol.14 (6), p.663-672
• Main Authors: Müller, Janis, Kirschner, Romina A., Berndt, Jan‐Philipp, Wulsdorf, Tobias, Metz, Alexander, Hrdina, Radim, Schreiner, Peter R., Geyer, Armin, Klebe, Gerhard
• Format: Article
• Language: English
• Subjects: adamantane; Affinity; Amino acids; Amino Acids - chemistry; artificial amino acids; Binding; Bonding; Chemical synthesis; Crystal structure; Crystallography, X-Ray; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - chemistry; diamondoids; Diamonds; Enzyme inhibitors; Inhibitors; Kinases; Lipophilicity; Membrane permeability; Molecular dynamics; Molecular Dynamics Simulation; NMR; Nuclear magnetic resonance; peptide inhibitors; Peptide synthesis; Peptides; Protein kinase A; Protein kinase inhibitors; Protein Kinase Inhibitors - pharmacology; Protein structure; Proteins; Secondary structure; Solvation; Structural analysis; Thermophoresis; Water chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800779

The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA‐containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid‐phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5‐fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen‐bond contacts to surrounding water molecules of the first solvation shell. The adamantane advantage: The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals by influencing their secondary structure and providing a unique spatial arrangement of exit vectors to attach other moieties. We designed and synthesized five novel peptidic DAA‐containing protein kinase A inhibitors and studied their properties by binding assays, NMR spectroscopy, and crystal structure analysis.