engleski

QSAR studies in a series of protein tyrosine kinase inhibitors

The design of specific inhibitors of protein tyrosine kinases (PTKIs) is important both for fundamental research and for therapeutic strategies development in treatment of diseases such as cancer. The aim of this work was to explore the relationships between molecular descriptors (MDs), drug-likeness scores (DLs) and ADMET parameters of PTKIs, derivatives of quinoline, quinazoline, pyrido- and pyrimido-pyrimidine, in correlation studies with their experimentally obtained IC50 of target kinase activity. MDs and DLs of investigated PTKIs were calculated using Molinspiration engines v2011.04 and v2011.06. TIs were calculated using DRAGON 6.0 software and ADMET properties by MedChem StudioTM and ADMET PredictorTM 6.5 (Simulations Plus, Inc., USA). All analyses were performed by OriginPro 8.0 (Origin Laboratories, USA). Protein tyrosine kinase inhibitors (PTKIs) (n = 28) were explored in correlation studies between computed molecular descriptors (MDs), topological indices (TIs), drug-likeness scores (DLs) and predicted ADMET parameters. 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. Lower kinase inhibitor-likeness scores (KI DLs 0.36 - 0.74) were computed for quinazoline derivatives. Significant correlations (R = 0.8869 – 0.9873) were obtained between MDs (Mr, V, TPSA) and topological indices (TIs), i.e. Wiener number (W), Randić connectivity index (X1) and Szeged index (Sz). ADMET Predictor analyses of PTKIs with multiple DLs revealed that they are CYP 2D6 and CYP 3A4 substrates, with CYP Risk 1, CYP Code D6, and TOX Risk 3 or 4. No significant correlations were found between MDs, TIs or ADMET parameters and IC50 of investigated compounds in series of investigated anilinoquinazolines.

Protein tyrosine kinase inhibito; small molecule; QSAR

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