Naslov
'The relationship between molecular descriptors, drug-likeness parameters and ADMET properties of small molecules, tyrosine kinase inhibitors' contributed short presentation in session 'Computational modelling for ADMET'

Autori
Jadrijevic-Mladar Takac, Milena

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

Izvornik
Program and Abstracts Booklet / Otto Kari (ur.). - Helsinki, Finland : University of Helsinki , 2011 / Program and Abstracts Booklet / Otto Kari (ur.). - Helsinki, Finland : University of Helsinki , 2011 - Helsinki, 2011, 36-37

Skup
Helsinki Drug Research 2011 Congress (HDR 2011) - Tools for ADMET and pharmaceutical nanotechnology

Mjesto i datum
Helsinki, Finska, 18.09.2011. - 20.09.2011

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
QSAR; protein tyrosine kinase inhibitors; small molecules; drug-likeness; ADMET properties

Sažetak
The relationship between molecular descriptors (MDs), topological indices (TIs), drug-likeness parameters (DLs) and ADMET properties of tyrosine kinase inhibitors (34 'small molecules') were analyzed with the aim to explore influences of molecular properties on their drug-likeness parameters with drugs of known biological activity and ADMET properties which could be relevant for their potential profile of anti-target activity. Different MDs and DLs were calculated using Molinspiration property engine v2011.04 and Molinspiration bioactivity score v2011.06, while TIs were calculated by means of ChemAxon software (www.chemicalize.org). ADMET properties were predicted by ADMET Predictor 5.5 (Simulations Plus, Inc., USA). All analyses were performed using OriginPro 8.0 software (Origin Laboratotries, USA). Study results showed significant collinearity between MDs (relative molecular mass, Mr, volume, V, n atoms and topological polar surface area, TPSA) and TIs, i.e. Wiener index (W), Haray index (H), Randić connectivity index (X1) and Szeged index (Sz) (r = 0.88691 - 0.98726). The decrease of kinase-likeness scores (KI dls) was observed with increase of TIs values. In a subgroup of quinazolin-4-amino derivatives study results revealed the optimal Log P 3.5 - 4.5, TPSA < 60, Mr < 400, and W and X1 up to 2000 and 15, respectively. The highest KI dls (0, 90 -1, 27) were calculated for pyrimido[5.4-d]pyrimidin-4-amine and pyrido [3.4-d]pyrimidin-4, 6-diamine derivatives, while for 12 quinazoline derivatives KI-dls with lower values (0, 36 to 0, 74) were obtained. The likeness with GPCR ligand (GPCR dls, 0, 21 – 0, 45), ion channel modulator (ICM dls, 0, 22 -0, 33) and enzyme inhibitor (EI dls, 0, 21 – 0, 36) were also revealed with nine molecules, out of total 34. Additional drug-likeness properties are most pronounced in a group of inhibitors with the highest KI dls (0, 9 - 1, 27). According to ADMET Predictor analyses, inhibitors with multiple drug-likeness scores were characterized as CYP 2D6 and CYP 3A4 substrates, with CYP Risk 1, CYP Code D6, and TOX Risk 3 or 4.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

Napomena
Najistaknutija izlaganja na posterima na HDR 2011 Kongresu bila su izabrana i autori su pozvani da temu prezentiaju i usmeno u programu kao 'Contributed short presentation' u trajanju od 15 min. Ovaj rad je bio izložen kao postersko priopćenje, ali je bio i usmeno izlagan 15 min u programu HDR 2011 sekcije 'Computational moddeling for ADMET'.

POVEZANOST RADA