Dual therapeutic approach to modulate Glycogen Synthase kinase −3 beta (GSK-3Β) and inhibitor of nuclear factor kappa kinase-beta (IKK-β) receptors by in silico designing of inhibitors

Cancer malignancies require the application of advanced strategies leading to the development of novel theranostic. Quite often drugs target a variety of receptors in the cell signaling cascades that could be explored to combat aggressive tumors. Herein, two receptors that are over-expressed during the diagnosis of breast cancer are used as the primary drug targets, inclusively Glycogen Synthase kinase −3 beta (GSK-3Β) and Inhibitor of nuclear factor kappa kinase-beta (IKK-β). Dual-targeting inhibitors pave the way for a challenging pathway in the treatment of aberrant tumor progression. The present study involves the observation of similarities in the structure of the receptors, along with the designing of novel therapeutics that act on them by molecular docking followed by a pharmacokinetic screening approach. A 3D QSAR modeling study is performed to approach the functionality of the bioactive conformer molecules. Additionally, Molecular Dynamic Simulation parameters are used for the validation of the drug complexes. Already available inhibitors are used as reference compounds and a library of analogs generated for these compounds from the PubChem database has been used for in silico designing of novel inhibitors. Molecular Docking and ADME analysis narrowed down the vast library of compounds to two specific classes of chemical compounds. Molecular Dynamic simulation studies used for the selection of the novel moieties showed significant superiority in their stability studies and binding trajectories resulted in two novel molecules A6 and B3 that could inhibit the kinase receptors. The current work involves computational designing of therapeutics targeting two major oncogenic proteins. [Display omitted] •It provides a possible insight into dual targeting therapy of two protein kinase receptors of EMT signalling pathways.•3D QSAR, molecular docking and MD simulation studies were implemented for extensive screening of the small molecule library.•Two specific classes of ligand molecules; the indolocarbazole and the pyrrolo-pyridine exhibited superior characteristics.•ual-targeting of the important oncogenic proteases might increase the efficacy of the treatment.