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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

Jadrijevic-Mladar Takač, Milena ; Takač, Vedran ; Barbarić, Monika ; Crnek-Kunstelj, Vesna Correlation Studies between ADMET Properties, Drug-likeness Scores and Molecular Descriptors in a Series of Protein Tyrosine Kinase Inhibitors // Periodicum biologorum / Vitale, Branko (ur.). 2013. str. 75-75

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.

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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

Indeksiranost