Naslov
Correlation Studies between Molecular Descriptors, Topological Indices and Drug-likeness Parameters of Protein Tyrosine Kinase Inhibitos

Autori
Bumber, Ivan ; Takač, Vedran ; Jadrijević-Mladar Takač, Milena ;

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

Izvornik
Book of Abstracts, ESPT Inagural Symposium: Pharmacogenomics: From Bench to Bedside, 4th BBBB Bled International Conference on Pharmaceutical Sciences. / Siest, Gerard ; Patrinos, George P. ; Marc, Janja - Ljubljana : Slovenian Pharmaceutical Society, 2011, 15-18

ISBN
978-961-92900-3-3

Skup
4th BBBB Bled International Conference on Pharmaceutical Sciences. ESPT Inaugural Symposium - Pharmacogenomics: From bench to bedside

Mjesto i datum
Bled, Slovenija, 30.09.2011. - 01.10.2011

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
QSAR; protein tyrosine kinase inhibitors; small molecule; molecular descriptors; toplological indices; drug-likeness

Sažetak
INTRODUCTION Protein tyrosine kinases play a fundamental role in signal transduction pathways regulating a number of cellular functions such as cell growth, differentiation and cell death. Hundreds of kinase inhibitors are currently in discovery and pre-clinical phases, and the number of kinase inhibitors which have been approved for the market, still remains low. The need to early predict the possible failure of a drug candidate and to reduce the risk of failure in late stages or after market introduction is becoming an absolute requirement in the drug discovery process from the initial phases of lead development, and great attention is paid to the characteristics of the compounds. In present work the relationship between molecular descriptors (MDs), topological indices (TIs) and drug-likeness parameters (DLs) of series (n = 34) of protein kinase inhibitors, ‘small molecules’, with different molecular features were analyzed and explored. MATERIALS AND METHODS The study includes 34 tyrosine kinase inhibitors. Drugs of ATC group L01 antineoplastic and immunomodulatory agents and tyrosine kinase inhibitors (‘small molecules’) in phase of clinical trials have been used in this study. Molecular descriptors (MDs) and drug-likeness scores (DLs) were calculated using Molinspiration molecular processing engine, ver. 2007.10., and topological indices (TIs) by ChemAxon, at www.chemicalize.org. All analyses were performed and data were graphed using OriginPro 8.0 software (Origin Laboratotries, USA). RESULTS AND DISCUSSION The relationship of molecular descriptors (MDs) (the parameter of lipophilicity, miLogP ; the topological polar surface area, TPSA ; the volume, V ; and the relative molecular mass, Mr), topological indices (TIs) (Wienner index, W ; Wiener polarity, Randić connectivity index, X1 ; Balaban index, J ; Szeged index, Sz ; Haray index, H ; Platt number, F) and parameters of drug-likeness scores (DLs) with drugs of known biological activity (the kinase inhibitor, KI dls ; the GPCR ligand, GPCR dls ; the nuclear receptor ligand, NRL dls ; and the ion channel modulator, ICM dls) were explored. The correlations of the MDs and TIs of the investigated compounds showed significant collinearity (Mr vs. V, R = 0.90311, y = 0.89684x –15.4867 ; Mr vs. Natom, R=0.91691, y=0.07126x – 0.50574 ; Mr vs. na, R = 0.91691, y = 0.07126x – 0.50574 ; Mr vs. W, R = 0.88691, y = 19, .96981 – 5553.16137 ; W vs. H, R = 0.93682, y = 0.01832x + 62.8596 ; W vs. Sz, R = 0.98726, y = 1.49543x + 127.11317). Correlation studies also showed the decrease in drug-likeness scores (KI dls) of investigated inhibitors with increase of molecular descriptors (MDs) and topological indices (TIs). The study results also revealed the most prominent kinase inhibitors in the group, the pyrido [3.4-d]pyrimidine derivatives HDS029 (28) and PD158780 (32). In the subgroup of quinazolin-4-amino derivatives (2-6, 13, 21, 25, 27, 31, 33), the study results revealed optimal values for miLogP 3.5 to 4.5, the topological polar surface area TPSA < 60, the Mr < 400, and values for topological Wiener (W) index and Randić index (X1) up to 2000 and 15, respectively. The kinase inhibitor-likeness scores (KI dls) were also correlared with other computed drug-likeness scores, and the collinear relationship was found with GPCR ligand-likeness scores (GPCR dls). CONCLUSIONS The results of correlation studies revealed the structural features and physicochemical properties relevant to activity of investigated compounds as protein tyrosine kinase inhibitors, and the possible use of this methodology in exploration of antitarget features of these inhibitors. 1.Krause DS, Van Ettern RA, Tyrosine kinases as target for cancer therapy, N. Engl. J. Med. 2005 ; 353: 172-187. 2.Sprous DG, Zhang J, Zhang L, Wang Z, Tepper MA, Kinase inhibitor recognition by use of a multivariable QSAR model, J. Mol. Graph. Model.. 2006 ; 24: 278-295.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

POVEZANOST RADA