A Novel Algorithm for the Virtual Screening of Extensive Small Molecule Libraries Against ERCC1/XPF Protein-Protein Interaction (PPI) for the Identification of Therapeutic Resistance-Bypassing Small Anticancer Molecules

Materials and

Methods

To this end, a novel hybrid virtual screening algorithm, conjoining ligand- and target-based approaches, was developed. All-atom molecular dynamics (MD) simulations were then run on the obtained hit molecules to reveal their structural and dynamic contributions within the binding site. MD simulations were followed by MM/GBSA calculations to qualify the change in binding free energies of the protein/ligand complexes throughout MD simulations Results: Results highlight new potential inhibitors AH-487/40936989 from the SPECS SC library, K219-1359 and K786-1161 from the ChemDiv Representative Set library as showing better activity than previously discovered ERCC1/XPF inhibitor, CHEMBL3617209.

Conclusion: The algorithm implemented in this study expands our comprehension of chemotherapeutic resistance and how to overcome it through identifying ERCC1/XPF inhibitors with the aim of enhancing chemotherapeutic impact giving hope for ameliorated cancer treatment outcomes.