How to design potent and selective DYRK1B inhibitors? Molecular modeling study

• Published in: Journal of molecular modeling Vol. 25; no. 2; pp. 41 - 12
• Main Authors: Szamborska-Gbur, Agnieszka, Rutkowska, Ewelina, Dreas, Agnieszka, Frid, Michael, Vilenchik, Maria, Milik, Mariusz, Brzózka, Krzysztof, Król, Marcin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2019; Springer Nature B.V
• Subjects: 8th conference on Modeling & Design of Molecular Materials (MDMM 2018); Amino Acid Sequence; Binding Sites; Cancer; Cell cycle; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer simulation; Crystal structure; Drug Design; Dyrk Kinases; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - chemistry; Glycogen Synthase Kinase 3 beta - metabolism; Homology; Humans; Inhibitors; Kinases; Modelling; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Medicine; Molecular Structure; Neoplasms - drug therapy; Neoplasms - metabolism; Original Paper; Phosphorylation - drug effects; Protein Binding; Protein Domains; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Proteins; Quinoline; Residues; Selectivity; Sequence Homology, Amino Acid; Structural analysis; Theoretical and Computational Chemistry; GSK3β; DYRK1B; Kinase inhibitor selectivity; Metadynamics simulations; Cancer cell quiescence; Homology modeling
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-018-3921-3

DYRK1B protein kinase is an emerging anticancer target due to its overexpression in a variety of cancers and its role in cancer chemoresistance through maintaining cancer cells in the G 0 (quiescent) state. Consequently, there is a growing interest in the development of potent and selective DYRK1B inhibitors for anticancer therapy. One of the major off-targets is another protein kinase, GSK3β, which phosphorylates an important regulator of cell cycle progression on the same residue as DYRK1B and is involved in multiple signaling pathways. In the current work, we performed a detailed comparative structural analysis of DYRK1B and GSK3β ATP-binding sites and identified key regions responsible for selectivity. As the crystal structure of DYRK1B has never been reported, we built and optimized a homology model by comparative modeling and metadynamics simulations. Calculation of interaction energies between docked ligands in the ATP-binding sites of both kinases allowed us to pinpoint key residues responsible for potency and selectivity. Specifically, the role of the gatekeeper residues in DYRK1B and GSK3β is discussed in detail, and two other residues are identified as key to selectivity of DYRK1B inhibition versus GSK3β. The analysis presented in this work was used to support the design of potent and selective azaindole-quinoline-based DYRK1B inhibitors and can facilitate development of more selective inhibitors for DYRK kinases.