Molecular hybridization assisted multi-technique approach for designing USP21 inhibitors to halt catalytic triad-mediated nucleophilic attack and suppress pancreatic ductal adenocarcinoma progression: A molecular dynamics study.

Aims: Pancreatic cancer, the 12th-most common cancer, globally, is highly challenging to treat due to its complex epigenetic, metabolic, and genomic characteristics. In pancreatic ductal adenocarcinoma, USP21 acts as an oncogene by stabilizing the long isoform of Transcription Factor 7, thereby activating the Wnt signaling pathway. This study aims to inhibit activation of this pathway through computer-aided drug discovery. Accordingly, four libraries of compounds were designed to target the USP21's catalytic domain (Cys221, His518, Asp534), responsible for its deubiquitinating activity.

Main Methods: Utilizing an array of computer-aided drug design methodologies, such as molecular docking, virtual screening, principal component analysis, molecular dynamics simulation, and dynamic cross-correlation matrix, the structural and functional characteristics of the USP21-inhibitor complex were examined. Following the evaluation of the binding affinities, 20 potential ligands were selected, and the best ligand was subjected to additional molecular dynamics simulation study.

Key Findings: The results indicated that the ligand-bound USP21 exhibited reduced structural fluctuations compared to the unbound form, as evident from RMSD, RMSF, Rg, and SASA graphs. ADMET analysis of the top ligand showed promising pharmacokinetic and pharmacodynamic profiles, good bioavailability, and low toxicity. The stable conformations of the proposed drug when bound to their target cavities indicate a robust binding affinity of -9.3 kcal/mol. The drug exhibits an elevated pKi value of 6.82, a noteworthy pIC value of 5.972, and a pKd value of 6.023 proving its high affinity and inhibitory potential towards the target.

Significance: In-vitro testing of the top compound (MOLHYB-0436) could lead to its use as a potential treatment for pancreatic cancer.