Drug Repurposing for Thioredoxin Interacting Protein Through Molecular Networking, Pharmacophore Modelling, and Molecular Docking Approaches

Abstract

Background: Diabetes Mellitus (DM) has emerged as one of the major causes behind global all-cause mortality between the age group of 20-79 years. Thioredoxin Interacting Protein (TXNIP) is a naturally occurring protein that primarily acts by binding to TRX protein, thereby inhibiting its ability to maintain the cellular reduced environment and subsequent oxidative stress, which leads to dysfunctional insulin production and pancreatic islet beta cell apoptosis. Objective: By inhibiting the levels of TXNIP, a search for new molecules was carried out by employing an in-silico approach. Methods: Molecular networking study was carried out using Cytoscape, wherein previously FDA-approved drugs were screened to check their ability to interact with TXNIP. This provided 14 drug molecules, which along with 11 previously obtained drug molecules that inhibit TXNIP, were subjected to pharmacophore generation. A pharmacophore was generated using the PharmaGist web server, which when visualised showed two hydrogen bond acceptors and one aromatic ring. Based on the generated pharmacophore model, we carried out virtual screening using ZINCPharmer. A total of 116 HITs were generated based on this pharmacophore model. We then subjected the 116 molecules to Molecular Docking against TXNIP (PDB: 4GEI) by using PyRx and the standard molecules, metformin and rosiglitazone. Results: Compared to the standard, we found 10 molecules that had a better binding affinity towards TXNIP. These 10 molecules were further taken for ADMET studies. From this, all 10 compounds showed good significant ADMET properties. Conclusion: From the preliminary studies, these 10 molecules showed good activity in the reversal of diabetes mellitus by reducing the levels of TXNIP.