Natural products as DNA methyltransferase inhibitors: a computer-aided discovery approach.

DNA methyltransferases (DNMTs) represent promising targets for the development of unique anticancer drugs. However, all DNMT inhibitors currently in clinical use are nonselective cytosine analogs with significant cytotoxic side-effects. Several natural products, covering diverse chemical classes, have indicated DNMT inhibitory activity, but these effects have yet to be systematically evaluated. In this study, we provide experimental data suggesting that two of the most prominent natural products associated with DNA methylation inhibition, (-)-epigallocathechin-3-gallate (EGCG) and curcumin, have little or no pharmacologically relevant inhibitory activity. We therefore conducted a virtual screen of a large database of natural products with a validated homology model of the catalytic domain of DNMT1. The virtual screening focused on a lead-like subset of the natural products docked with DNMT1, using three docking programs, following a multistep docking approach. Prior to docking, the lead-like subset was characterized in terms of chemical space coverage and scaffold content. Consensus hits with high predicted docking affinity for DNMT1 by all three docking programs were identified. One hit showed DNMT1 inhibitory activity in a previous study. The virtual screening hits were located within the biological-relevant chemical space of drugs, and represent potential unique DNMT inhibitors of natural origin. Validation of these virtual screening hits is warranted.