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'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' (CROSBI ID 593020)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija

Jadrijevic-Mladar Takac, Milena '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' // 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 (ur.). Helsinki, 2011. str. 36-37

Podaci o odgovornosti

Jadrijevic-Mladar Takac, Milena

engleski

'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'

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.

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

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'.

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Podaci o prilogu

36-37.

2011.

objavljeno

Podaci o matičnoj publikaciji

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:

Podaci o skupu

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

predavanje

18.09.2011-20.09.2011

Helsinki, Finska

Povezanost rada

Farmacija

Poveznice