Abstract
Protein tyrosine kinase (p56lck) is known for its role in T cells, in which deficiency of Lck is shown to impair cell activation via T-cell antigen receptor. Benzothiazoles have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP binding site of protein kinases. ATP binding site of protein kinases provided an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of p56lck. QSAR studies were performed on a set of 45 analogs of benzothiazoles using Molecular Operating Environment (MOE) software. The models developed gave good predictive correlation coefficient (r2pred) of 0.765. A training set of 35 compounds was developed with correlation coefficient (r2) of 0.983 and a significant cross validated correlation coefficient (q2) of 0.723. Various sets of descriptors to meet the orthogonality of model to ensure that each descriptor is encoding different properties from others were used. Subdivided surface area, water accessible surface area, partial charge and adjacency and distance matrix were the major contributing descriptors. Leave one out and $ Z-score values were used to optimize the model. The model developed to predict the structural features of benzothiazole, revealed useful information about the structural features required for the molecules to inhibit p56lck. Major contributing descriptors were subdivided surface area, partial charges and water accessible surface area.
Keywords: CD4 molecules, cell regulatory processes, QSAR model, ATP binding, benzothiazole derivatives
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