RESUMEN
WIF1 (Wnt inhibitory factor 1) is a potent tumour suppressor gene which is epigenetically silenced in numerous malignancies. The associations of WIF1 protein with the Wnt pathway molecules have not been fully explored, despite their involvement in the downregulation of several malignancies. In the present study, a computational approach encompassing the expression, gene ontology analysis and pathway analysis is employed to obtain an insight into the role of the WIF1 protein. Moreover, the interaction of the WIF1 domain with the Wnt pathway molecules was carried out to ascertain the tumour-suppressive role of the domain, along with the determination of their plausible interactions. Initially, the protein-protein interaction network analysis endowed us with the Wnt ligands (such as Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt8a and Wnt9a), along with the Frizzled receptors (Fzd1 and Fzd2) and the low-density lipoprotein complex (Lrp5/6) as the foremost interactors of the protein. Further, the expression analysis of the aforementioned genes and proteins was determined using The Cancer Genome Atlas to comprehend the significance of the signalling molecules in the major cancer subtypes. Moreover, the associations of the aforementioned macromolecular entities with the WIF1 domain were explored using the molecular docking studies, whereas the dynamics and stability of the assemblage were investigated using 100 ns molecular dynamics simulations. Therefore, providing us insights into the plausible roles of WIF1 in inhibiting the Wnt pathways in various malignancies.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Neoplasias , Vía de Señalización Wnt , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Simulación del Acoplamiento Molecular , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Neoplasias/genéticaRESUMEN
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-ß). 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.