2. Academic Validation
  3. Shedding light on the binding mechanism of kinase inhibitors BI-2536, Volasetib and Ro-3280 with their pharmacological target PLK1

Shedding light on the binding mechanism of kinase inhibitors BI-2536, Volasetib and Ro-3280 with their pharmacological target PLK1

  • J Photochem Photobiol B. 2022 Jul;232:112477. doi: 10.1016/j.jphotobiol.2022.112477.
Jesús Fernández-Sainz 1,  Pedro J Pacheco-Liñán 1,  José M Granadino-Roldán 2,  Iván Bravo 1,  Jaime Rubio-Martínez 3,  José Albaladejo 4,  Andrés Garzón-Ruiz 5
Affiliations

Affiliations

  • 1 Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Cronista Ballesteros Gómez, 1, 02071 Albacete, Spain.
  • 2 Departamento de Química Física y Analítica, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus "Las Lagunillas" s/n, 23071 Jaén, Spain.
  • 3 Departament de Ciència dels Materials i Química Física, Universitat de Barcelona (UB), Institut de Recerca en Quimica Teorica i Computacional (IQTCUB), Martí i Franqués 1, 08028 Barcelona, Spain.
  • 4 Departamento de Química Física, Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain.
  • 5 Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Cronista Ballesteros Gómez, 1, 02071 Albacete, Spain. Electronic address: Andres.Garzon@uclm.es.
PMID: 35644070 DOI: 10.1016/j.jphotobiol.2022.112477
Abstract

In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain. All the determined binding constants are higher for the kinase inhibitors than for their competitor for the active center (ATP) being BI-2536 and Volasertib the inhibitors that showed more affinity for PLK1. Calculated binding free energies confirmed the higher affinity of PLK1 for BI-2536 and Volasertib than for ATP. The higher affinity of the inhibitors to PLK1 compared to ATP was mainly attributed to stronger van der Waals interactions. Results may help with the challenge of designing and developing new kinase inhibitors more effective in clinical Cancer therapy.

Keywords

BI-2536; BI-6727; Fluorescence spectroscopy; Molecular modeling; PLK1; Ro-3280; Volasertib.

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