Harnessing virtual screening for the targeted discovery of cisplatin adjuvants from marine invertebrates

Cisplatin is a widely used chemotherapeutic agent that acts by damaging DNA, ultimately leading to apoptosis. However, studies with patient tissues have shown positive correlation between overexpression of the DNA repair enzyme ERCC1 and resistance to cisplatin. In this study, we have used virtual screening (VS) of 3D libraries derived from MarinLit targeting a protein binding pocket critical for recruitment of ERCC1. VS results were used in the chemotaxonomic selection of “prioritized” organisms as a pre-filter to in vitro HTS of marine natural products disrupting this protein-protein interaction. This methodology has provided a validation of the predictive value of the VS, a six-fold reduction of screening burden and a near two-fold increase in validated hit rate relative to “non-prioritized” organisms. We have also identified several potential leads from known compounds to discover disruptors of this DNA repair mediated resistance in cancer.