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Rational drug design of Axl tyrosine kinase type I inhibitors as promising candidates against cancer
(2020)
The high level of Axl tyrosine kinase expression in various cancer cell lines makes it an attractive target for the development of anti-cancer drugs. In this study, we carried out several sets of in silico screening for the ATP-competitive Axl kinase inhibitors based on different molecular docking protocols. The best drug-like candidates were identified, after parental structure modifications, by their highest affinity to the target protein. We found that our newly designed compound R5, a derivative of the R428 patented analog, is the most promising inhibitor of the Axl kinase according to the three molecular docking algorithms applied in the study. The molecular docking results are in agreement with the molecular dynamics simulations using the MM-PBSA/GBSA implicit solvation models, which confirm the high affinity of R5 toward the protein receptor. Additionally, the selectivity test against other kinases also reveals a high affinity of R5 toward ABL1 and Tyro3 kinases, emphasizing its promising potential for the treatment of malignant tumors.
Chemical processes mostly happen in fluid environments where reaction partners encounter via diffusion. The bimolecular encounters take place at a nanosecond time scale. The chemical environment (e.g., solvent molecules, (counter)ions) has a decisive influence on the reactivity as it determines the contact time between two molecules and affects the energetics. For understanding reactivity at an atomic level and at the appropriate dynamic time scale, it is crucial to combine matching experimental and theoretical data. Here, we have utilized all-atom molecular-dynamics simulations for accessing the key time scale (nanoseconds) using a QM/MM-Hamiltonian. Ion pairs consisting of a radical ion and its counterion are ideal systems to assess the theoretical predictions because they reflect dynamics at an appropriate time scale when studied by temperature-dependent EPR spectroscopy. We have investigated a diketone radical anion with its tetra-ethylammonium counterion. We have established a funnel-like transition path connecting two (equivalent) complexation sites. The agreement between the molecular-dynamics simulation and the experimental data presents a new paradigm for ion–ion interactions. This study exemplarily demonstrates the impact of the molecular environment on the topological states of reaction intermediates and how these states can be consistently elucidated through the combination of theory and experiment. We anticipate that our findings will contribute to the prediction of bimolecular transformations in the condensed phase with relevance to chemical synthesis, polymers, and biological activity.