In silico drug repurposing by combining machine learning classification model and molecular dynamics to identify a potential OGT inhibitor.

Abstract

O-linked N-acetylglucosamine (O-GlcNAc) is a unique intracellular post-translational glycosylation at the hydroxyl group of serine or threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O-GlcNAc transferase (OGT) is responsible for adding GlcNAc, and anomalies in this process can lead to the development of diseases associated with metabolic imbalance, such as diabetes and cancer. Repurposing approved drugs can be an attractive tool to discover new targets reducing time and costs in the drug design. This work focuses on drug repurposing to OGT targets by virtual screening of FDA-approved drugs through consensus machine learning (ML) models from an imbalanced dataset. We developed a classification model using docking scores and ligand descriptors. The SMOTE approach to resampling the dataset showed excellent statistical values in five of the seven ML algorithms to create models from the training set, with sensitivity, specificity and accuracy over 90% and Matthew's correlation coefficient greater than 0.8. The pose analysis obtained by molecular docking showed only H-bond interaction with the OGT C-Cat domain. The molecular dynamics simulation showed the lack of H-bond interactions with the C- and N-catalytic domains allowed the drug to exit the binding site. Our results showed that the non-steroidal anti-inflammatory celecoxib could be a potentially OGT inhibitor.