The relationship between molecular descriptors, drug-likeness parameters and ADMET properties of small molecules, tyrosine kinase inhibitors (CROSBI ID 592988)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Jadrijevic-Mladar Takac, Milena ; Takač, Vedran ; Bumber, Ivan ;
engleski
The relationship between molecular descriptors, drug-likeness parameters and ADMET properties of small molecules, tyrosine kinase inhibitors
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
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Podaci o prilogu
36-37.
2011.
objavljeno
Podaci o matičnoj publikaciji
HDR 2011 Program and Abstracts Booklet
Otto Kari
Helsinki: University of Helsinki
Podaci o skupu
Helsinki Drug Research 2011 Congress (HDR 2011) - Tools for ADMET and pharmaceutical nanotechnology
poster
18.09.2011-20.09.2011
Helsinki, Finska