engleski

Correlation studies between ADMET properties, drug-likeness scores and molecular descriptors in a series of protein tyrosine kinase inhibitors

Kinases are the most exciting targets in drug discovery because they are key drivers of malignant transformation and major contributors to a variety of other human pathologies. Over recent years there has been remarkable progress in the medicinal chemistry design of selective protein tyrosine kinase inhibitors (PTKIs). Small molecule inhibitors attracted significant interest therapeutically and highly selective PTKIs are valuable probes and tools in anti-cancer and anti-inflammatory drug discovery. There are now over 20 kinase inhibitor drugs on the market, but numerous inhibitors are currently in discovery and preclinical phases, and the number of inhibitors that has been approved for the market, still remains low. In this study we explored molecular descriptors (MDs), drug-likeness scores (dls) and ADMET parameters in correlation studies that could be relevant for target and potential anti-target profile of investigated PTKIs. MDs and dls of investigated PTKIs were calculated using Molinspiration property engine v2013.09 and Molinspiration bioactivity score v2011.06 and TIs by Chemicalize.org/Properties Viewer (ChemAxon). The ADMET properties were computed by MedChem StudioTM and ADMET PredictorTM 7.0 (SimulationsPlus, Inc., USA). All analyses were performed using OriginPro 8.0 software (Origin Laboratories, USA). Significant relationships (r = 0.88691-0.98726) were obtained between MDs (Mr, V, TPSA) and toplological indices (TIs), i.e. Wiener number (W), Randić connectivity index (1) and Szeged index (Sz). Among investigated PTKIs with basic bicyclic ring systems (quinoline, quinazoline, pyrido- and pyrimido-pyrimidine), the highest scores for kinase inhibitor likeness (KI-dls 0.90-1.27) were computed for pyrimido[5.4-d]pyrimidin-4-amine and pyrido[3.4-d]pyrimidin-4, 6-diamines. For these compounds dls with GPCR ligand (0.21-0.45), ion channel modulator (0.22-0.33) and enzyme inhibitor (0.21-0.36) were also computed. The KI-dls with lower values (0, 36-0, 74) were computed for quinazoline derivatives (Log P 3.5-4.5, TPSA<60, Mr<400). ADMET Predictor analyses of PTKIs with multiple drug-likeness scores revealed that they are CYP 2D6 and CYP 3A4 substrates, with CYP Risk 1, TOX Risk 3 or 4. No significant correlations were found between MDs, TIs or ADMET parameters and IC50 of investigated compounds in a series of anilinoquinazolines.

Protein tyrosine kinase inhibitors; small molecules; ADMET parameters; molecular descriptors; drug-likeness; QSAR

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