Discovery of new potential UCHL-3 inhibitors via virtual screening, molecular dynamics and binding mode analysis for cancer treatment














The research team led by Dr. Reem Arafa, Professor of Biomedical Sciences and Director of the Drug Design and Discovery Laboratory at Zewail City, has published a new paper titled “Targeting homologous recombination (HR) repair mechanism for cancer treatment: discovery of new potential UCHL-3 inhibitors via virtual screening, molecular dynamics and binding mode analysis” In the Journal of Biomolecular Structure and Dynamics

UCHL3 (ubiquitin C-terminal hydrolase-L3) is a deubiquitinating enzyme, involved in the homologous recombination repair mechanism of double-strand breaks (DBS) of the DNA. Multiple studies indicated that UCHL3 inhibitors could be used in combination therapy with high therapeutic efficacy against cancer, thus highlighting the validity of directing research against UCHL3 as a druggable target in oncology.


In this study, a combination of virtual screening methods was utilized to pinpoint potential UCHL3 inhibitors. A series of UCHL3 ligands were identified by applying a combination of cheminformatics and molecular modeling filtration techniques to a ChemBl database of over two million small molecules viz.


The selection of the chemical database under investigation was based on Lipinski's Rule of Five, Veber’s rule, pharmacophore model, Hierarchical molecular docking, Pan-assay Interference Compounds (PAINS) alerts, toxicity filter, and single-point Molecular mechanics Poisson/Boltzmann surface area (MM/PBSA) docking pose rescoring.


This multi-layer filtration strategy led to the identification of twenty-one compounds as potential UCHL3 inhibitors subsequently subjected to a 50 ns molecular dynamics (MD) simulations that predict the stability of their ligand-protein complexes. Furthermore, MM/PBSA calculations, based on MD trajectories, were performed, and the energy contribution per residue to the binding energy was calculated. Three compounds: 1, 2 and 3 were finally recognized as having the highest potential of being UCHL3 inhibitors.