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.
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