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Structure-based Drugs Design Studies on Spleen Tyrosine Kinase Inhibitors

[ Vol. 13 , Issue. 9 ]

Author(s):

Letícia Cristina Assis, Letícia Santos Garcia, Daiana Teixeira Mancini, Tamiris Maria Assis, Daniela Rodrigues Silva, Giovanna Gajo Cardoso, Alexandre Alves de Castro, Teodorico Castro Ramalho and Elaine Fontes Ferreira da Cunha   Pages 845 - 858 ( 14 )

Abstract:


A quantitative structure-activity relationship analysis has been applied to a series of 97 imidazopyridine analogous Spleen tyrosine kinase (Syk) inhibitors, the enzyme responsible for the signal transduction of classic immunoreceptors. The deregulation of Syk is associated with several pathologies, among which uncontrolled tumor cell growth stands out. The most advanced Syk inhibitor, fostamatinib, has proven efficient in multiple therapeutic indications, but its clinical evolution is still in process. In this context it is necessary to search for new potent inhibitors andin this work we have developed and validated 4D-QSAR models in order to obtain pharmacophoricfeatures that can enhance the potency of the imidazopyridine compounds. The conformations obtained by molecular dynamic simulation were overlapped in a virtual three dimensional box comprised of 1 Å cells, according to the six trial alignments. The models were generated by a combined genetic algorithm (GA) and partial least squares (PLS) regression technique. The best models generated show good adjusted cross-validate value (q2adjusted) and correlation coefficient value (R2). Analyzing the descriptors it can be observethat the nonpolar substituents are detrimental for activity of these compounds, suggesting hydrophilic regions in the Syk active site.

Keywords:

Molecular modeling, QSAR, molecular dynamics, genetic function approximation, spleen tyrosine kinase, imidazopyridine.

Affiliation:

Dept. of Chemistry, Federal University of Lavras, C.P. 3037, CEP 37200-000, Lavras, Minas Gerais, Brazil.

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