Naslov
Relationships between Molecular Descriptors, Drug-likeness, ADMET Parameters and Biological Activity of Tyrosine Kinase Inhibitors in a Series of Quinoline, Quinazoline, Pyrido- and Pyrimido-pyrimidine Derivatives

Autori
Jadrijevic-Mladar Takac, Milena ; Takac, Vedran ; Barbaric, Monika ; Crnek-Kunstelj, Vesna

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

Izvornik
Abstracts, Poster Session Online, Virtual Gallery, 5th PSWC / Joseph T. DiPiro - Den Haag : International Pharmaceutical Federation (FIP), 2014, PC-005

Skup
5th FIP Pharmaceutical Sciences World Congress (PSWC), Pharmaceutical Sciences beyond 2020 – The Rise of a New Era in Healthcare

Mjesto i datum
Melbourne, Australija, 13.04.2014. - 16.04.2014

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Drug design and discovery; Protein tyrosine kinase inhibitors; QSAR; ADMET; Molecular descriptors; Drug-likeness

Sažetak
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). Significant correlations (r = 0.8869-0.9873) were obtained between MDs (molecular mass, Mr ; volume, V and topological polar surface area, TPSA) and TIs, i.e. Wiener number (W), Randić connectivity index (X1) and Szeged index (Sz). 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 KI-DLs (0.36-0.74) were computed for quinazoline derivatives. 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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Farmacija

POVEZANOST RADA