Naslov
Correlation Studies between ADMET Properties, Drug-likeness Scores and Molecular Descriptors in a Series of Protein Tyrosine Kinase Inhibitors

Autori
Jadrijevic-Mladar Takač, Milena ; Takač, Vedran ; Barbarić, Monika ; Crnek-Kunstelj, Vesna

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Final Program and Abstract Book, 7th Croatian Congress of Pharmacology with International Participation, Period. biol. Vol. 115, Suppl 3 / Vitale, Branko - Zagreb : Hrvatsko prirodoslovno društvo ; Institut Ruđer Bošković, 2013, 75-75

Skup
7th Croatian Congress of Pharmacology with International Participation

Mjesto i datum
Zagreb, Hrvatska, 18.09.2013. - 21.09.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Protein tyrosine kinase inhibitors; PTKI; molecular descriptors; topological indices; drug-likeness; ADMET
(Protein tyrosine kinase inhibitors; PTKI; molecular descriptors; topological indices. drug-likeness; ADMET)

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA