5yvc Citations

Protein ligand interaction analysis against new CaMKK2 inhibitors by use of X-ray crystallography and the fragment molecular orbital (FMO) method.

J Mol Graph Model 99 107599 (2020)
Related entries: 5yv8, 5yv9, 5yva, 5yvb

Cited: 8 times
EuropePMC logo PMID: 32348940

Abstract

CaMKK2 (calcium/calmodulin dependent protein kinase kinase 2) is a serine/threonine protein kinase that regulates phosphorylation of CaM kinases (CaMKs) such as CaMKI, CaMKIV, and AMP-activated protein kinase (AMPK). From a pathological perspective, CaMKK2 plays a role in obesity, diabetes, and prostate cancer. Therefore, CaMKK2 is an attractive target protein for drug design. Here, we tried to find new CaMKK2 inhibitors by using ligand-based and structure-based drug design approaches. From the in silico hit compounds, we identified new inhibitors by using a CaMKK2 kinase assay. We solved X-ray crystallography structures of the CaMKK2-inhibitor complexes and performed Fragment Molecular Orbital (FMO) calculations to analyze the protein-ligand interactions, identify the key residues in inhibitor binding, and quantitatively measure their contribution. We experimentally determined five CaMKK2-inhibitor structures and calculated the binding energies of the inhibitors by the FMO method plus MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach. The results showed a high correlation (R = -0.89) between experimentally measured inhibitory activity (pIC50) and the predicted ligand binding energy. We then quantitatively evaluated the contribution of each binding site residue in CaMKK2 by the IFIE (Inter-fragment Interaction Energy)/PIEDA (Pair Interaction Energy Decomposition Analysis) method. The IFIE values indicated that Lys194 and Glu236, which formed hydrogen bonds with the carboxylate groups of the inhibitors, were key residues for ligand binding. PIEDA revealed that the dispersion interaction of inhibitors with hydrophobic residues, such as Ile171, Phe267, and Leu319, contributed highly to ligand binding; we considered that this was due to CH-π interactions with methoxy groups and/or aromatic rings contained in our CaMKK2 inhibitor. These results from the quantitative interaction analysis by the FMO method are useful not only for future CaMMK2 inhibitor development but for application of the FMO method to in silico drug design.

Reviews citing this publication (4)

  1. Nanopore Technology for the Application of Protein Detection. Zeng X, Xiang Y, Liu Q, Wang L, Ma Q, Ma W, Zeng D, Yin Y, Wang D. Nanomaterials (Basel) 11 1942 (2021)
  2. Regulation and role of CAMKK2 in prostate cancer. Pulliam TL, Goli P, Awad D, Lin C, Wilkenfeld SR, Frigo DE. Nat Rev Urol 19 367-380 (2022)
  3. Nanopore sensors for single molecular protein detection: Research progress based on computer simulations. Hu G, Yan H, Xi G, Gao Z, Wu Z, Lu Z, Tu J. IET Nanobiotechnol 17 257-268 (2023)
  4. Molecular Modeling Insights into the Structure and Behavior of Integrins: A Review. Tvaroška I, Kozmon S, Kóňa J. Cells 12 324 (2023)

Articles citing this publication (4)

  1. 1,4-Dideoxy-1,4-imino-D- and L-lyxitol-based inhibitors bind to Golgi α-mannosidase II in different protonation forms. Kóňa J, Šesták S, Wilson IBH, Poláková M. Org Biomol Chem 20 8932-8943 (2022)
  2. Systemic Ablation of Camkk2 Impairs Metastatic Colonization and Improves Insulin Sensitivity in TRAMP Mice: Evidence for Cancer Cell-Extrinsic CAMKK2 Functions in Prostate Cancer. Pulliam TL, Awad D, Han JJ, Murray MM, Ackroyd JJ, Goli P, Oakhill JS, Scott JW, Ittmann MM, Frigo DE. Cells 11 1890 (2022)
  3. Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors. Yuan Z, Chen X, Fan S, Chang L, Chu L, Zhang Y, Wang J, Li S, Xie J, Hu J, Miao R, Zhu L, Zhao Z, Li H, Li S. Int J Mol Sci 25 671 (2024)
  4. Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors. Hengphasatporn K, Aiebchun T, Mahalapbutr P, Auepattanapong A, Khaikate O, Choowongkomon K, Kuhakarn C, Meesin J, Shigeta Y, Rungrotmongkol T. ACS Omega 8 19645-19655 (2023)