Combining a QSAR Approach and Structural Analysis to Derive an SAR Map of Lyn Kinase Inhibition.

Imane Naboulsi,Abdelaziz Yasri,Aziz Aboulmouhajir,Lamfeddal Kouisni,Faouzi Bekkaoui

doi:10.3390/molecules23123271

Abstract

Lyn kinase, a member of the Src family of protein tyrosine kinases, is mainly expressed by various hematopoietic cells, neural and adipose tissues. Abnormal Lyn kinase regulation causes various diseases such as cancers. Thus, Lyn represents, a potential target to develop new antitumor drugs. In the present study, using 176 molecules (123 training set molecules and 53 test set molecules) known by their inhibitory activities (IC50) against Lyn kinase, we constructed predictive models by linking their physico-chemical parameters (descriptors) to their biological activity. The models were derived using two different methods: the generalized linear model (GLM) and the artificial neural network (ANN). The ANN Model provided the best prediction precisions with a Square Correlation coefficient R2 = 0.92 and a Root of the Mean Square Error RMSE = 0.29. It was able to extrapolate to the test set successfully (R2 = 0.91 and RMSE = 0.33). In a second step, we have analyzed the used descriptors within the models as well as the structural features of the molecules in the training set. This analysis resulted in a transparent and informative SAR map that can be very useful for medicinal chemists to design new Lyn kinase inhibitors.

Highlights

Many signaling pathways transmit extracellular signals by altering the phosphorylation state of tyrosine residues
Topological and electronic molecular descriptors combined with a generalized linear model (GLM)
Topological and electronic molecular descriptors combined with a method and artificial neural network (ANN) method were used for modeling and predicting Lyn kinase inhibitors

Summary

Introduction

Many signaling pathways transmit extracellular signals by altering the phosphorylation state of tyrosine residues. Phosphorylation of proteins in which tyrosine amino acid residue is phosphorylated by tyrosine kinases by the addition of a covalently bound phosphate group of ATP (adenosine triphosphate) [1], accounts only 0.1% of total protein phosphorylation in mammals. Tyrosine kinases play a key role in the regulation of many biological phenomena such as cell proliferation, differentiation and motility. Non-receptor tyrosine kinases (NRTK) [2]. The existence of multiple conformations of kinases (active and non-active state) and the structural diversity of the ATP-binding site as well as the activation loop provide different strategies for designing inhibitors. By binding into the active site of the receptor tyrosine kinase, block the Molecules 2018, 23, 3271; doi:10.3390/molecules23123271 www.mdpi.com/journal/molecules

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Discussion

Conclusion