Correlation Studies between ADMET Properties, Drug-likeness Scores and Molecular Descriptors in a Series of Protein Tyrosine Kinase Inhibitors (CROSBI ID 605433)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | domaća recenzija
Podaci o odgovornosti
Jadrijevic-Mladar Takač, Milena ; Takač, Vedran ; Barbarić, Monika ; Crnek-Kunstelj, Vesna
engleski
Correlation Studies between ADMET Properties, Drug-likeness Scores and Molecular Descriptors in a Series of Protein Tyrosine Kinase Inhibitors
Introduction: The design of specific inhibitors of protein tyrosine kinases (PTKI) is important both for fundamental research and for developing therapeutic strategies for the treatment of diseases such as cancer. Numerous PTKIs are currently in discovery and preclinical phases, and the number of PTKIs that have been approved for the market, still remains low. In this study we explored molecular descriptors (MDs), drug-likeness (dls) and ADMET parameters in correlation studies that could be relevant for potential anti-target profile of investigated PTKIs. Materials and methods: Molecular descriptors and drug-likeness parameters of a series of PTKIs were calculated using Molinspiration property engine v2011.04 and Molinspiration bioactivity score v2011.06. The ADMET properties were computed by MedChem StudioTM and ADMET PredictorTM 6.0 (Simulations Plus, Inc., USA). All analyses were performed using OriginPro 8.0 software (Origin Laboratories, USA). Results: Significant relationships (r = 0.88691-0.98726) were obtained between MDs (Mr, V, TPSA) and toplological indices, TIs (W, X1, 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). Conclusions: ADMET Predictor analyses of PTKIs with multiple drug-likeness scores revealed that they are CYP 2D6 and CYP 3A4 substrates, with CYP Risk 1, CYP Code D6, and TOX Risk 3 or 4.
Protein tyrosine kinase inhibitors; PTKI; molecular descriptors; topological indices. drug-likeness; ADMET
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Podaci o prilogu
75-75.
2013.
nije evidentirano
objavljeno
Podaci o matičnoj publikaciji
Periodicum biologorum
Vitale, Branko
Zagreb: Hrvatsko prirodoslovno društvo ; Institut Ruđer Bošković
0031-5362
Podaci o skupu
7th Croatian congress of pharmacology with international participation
poster
18.09.2013-21.09.2013
Zagreb, Hrvatska
Povezanost rada
Kemija, Temeljne medicinske znanosti, Farmacija