3D QSAR and molecular docking study of benzomaide derivatives as potent inhibitors of Btk kinase

Adnane Aouidate, Adib ghaleb, Mounir Ghamali, Samir Chtita, Abdellah Ousaa, M’barek Choukrad, Abdelouahid sbai, Mohamed Bouachrine, Tahar Lakhlifi

Abstract


Bruton’s tyrosine kinase (Btk) is an important enzyme in Blymphocyte development and differentiation. Furthermore, Btk expression is considered essential for the proliferation and survival of these cells. Btk inhibition has become an attractive strategy for treating autoimmune diseases, B-cell leukemia and lymphomas, With the objective of undeerstand the Btk inhibitory activity of benzamide derivatives. A series of fourty-four Btk inhibitors reported in the literature containing benzamide scaffold was studied by using two computational techniques, namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) was developed using thirty-three molecules having pIC50 ranging from 2.000 to 5.236. The best generated CoMFA model exhibit conventional determination coefficients R2 of 0.92 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.61, respectively. Moreover, the predictive ability of this model was evaluated by the external validation using a test set of eleven compounds with predicted determination coefficients R2test of 0.76. Besides, yrandomization test was also performed to validate our 3D-QSAR models. The most active compound was docked into the active site of the protein (PDB ID: 5P9J) to confirm those obtained results from 3D-QSAR model and elucidate the binding mode between this kind of compounds and the Btk enzyme. These satisfactory results are not offered help only to understand the binding mode of benzamide series compounds into this kind of targets, but provide information to design new potent Btk inhibitors.


Keywords


CoMFA ; Molecular docking ; Btk ; Drug design ; Benzamide

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Online ISSN: 2605-6895

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