Exploring Target-Based Screening, Molecular Dynamics Simulation and Principal Component Analysis for Drug Repurposing in NUT Midline Carcinoma

Purpose: NMC, a particularly malignant and invasive cancer resulting from the fusion of the NUT and BRD4 genes, yields a fusion protein that influences cell growth and regulates transcription. The deregulation of this protein has been documented in numerous cancerous conditions. The BD1 domain of BRD4-containing proteins has been demonstrated to bind to acetylated lysine residues on histone proteins, thereby impacting gene expression and chromatin remodeling. Methods: The DrugRep database was used for target-based screening (TBS) of FDA-approved drugs. CurPocket, an integrated tool within DrugRep, was employed to automatically identify potential binding pockets, and docking was performed using AutoDock Vina 1.1.2. SwissADME tools were utilized to assess pharmacokinetics and drug-likeness attributes. Additionally, the GROMACS and Galaxy platforms were employed for MD simulations and principal component analysis, respectively. Results: The TBS technique was used to evaluate 100 drug candidates for human intestinal absorption and blood-brain barrier permeability using the Egan-Egg model. 84 met the filtration criteria, and the drug-likeness models narrowed the pool to 48. Toxicophoric parameters, including the PAINS and Brenk alerts, further refined the subset of potential drugs to 39. The lead-likeness criteria identified five drugs, which were evaluated based on binding free energy and hydrogen bond analysis. MD simulation and PCA led to more in-depth evaluations, ultimately leading to the selection of estrone as a potential repurposed drug for NMC. Conclusion: These results indicated that ataluren may be a suitable candidate for the development of a therapeutic drug to treat NMC. However, additional laboratory experiments are required to validate these preliminary findings.