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The use of NMR chemical shifts in correlation studies with molecular descriptors, drug-likeness scores and ADMET properties in a series of protein tyrosine kinase inhibitors

Numerous protein tyrosine kinase inhibitors are currently in discovery and preclinical phases, and the number of kinase inhibitors which have been approved for the market, still remains low.The need for early predictions of the possible failure of a drug candidate with the aim of reducing the risk of failure in late stages or after introduction at market is becoming an absolute requirement in drug discovery process from the initial phases of lead candidate development.The aim of this study is to explore the use of the NMR chemical shifts in correlation studies with molecular descriptors, drug-likeness parameters and ADMET properties which could be relevant for potential profile of anti-target activities of investigated protein tyrosine kinase inhibitors.Molecular descriptors and drug-likeness parameters of a series of tyrosine kinase inhibitors, derivatives of (n = 30) were calculated using Molinspiration property engine v2011.04 and Molinspiration bioactivity score v2011.06. ADMET properties were predicted by ADMET Predictor 5.5 (Simulations Plus, Inc., USA). NMR chemical shifts were extrapolated from real 1H NMR spectra recorded in deuterated solvents.In a group of small molecules with basic bicyclic ring systems, ie. quinoline, quinazoline, pyrido- and pyrimido-pyrimidine derivatives, the highest scores of kinase inhibitor likeness (KI-ls) were calculated for pyrido- and pyrimido-pyrimidine derivatives. In addition the study results revealed that molecules with high KI-ls scores (0.80-1.27) also have drug-likeness with GPCR ligand (0.21-0.45), ion channel modulator (0.22-0.33) and enzyme inhibitor (0.21-0.36).The influence of substituents attached on the basic bicyclic ring systems were analyzed by NMR spectroscopy, and the corresponding 1H NMR chemical shifts of the basic bicyclic systems were used in correlation studies, and proved to be a valuable descriptor in predicting target and anti-target properties of these molecules.

QSAR; protein tyrosine kinase inhibitors; small molecules; molecular descriptors; NMR chemical shifts; drug-likeness; ADMET parameters

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