Epigenetic Drugs, and Their Virtual Screening Study Retrieved from ZINC Database Along with an AutoDock Study of the Best Inhibitor

Objective: Over the last 30 years, cancer epigenetics research has grown extensively. Epigenetic events are involved throughout the entire human lifecycle, from embryogenesis to adulthood. It is note-worthy to recognize that epigenetic misregulation could substantiate the development of cancer and we need to continue to look for anti-neoplastic epi-drugs. Taking into consideration this phenomenon, our first aim is to search for an effective epi-drugs by virtual screening from ZINC database and to explore the validity of the virtual screening. The second aim is to explore a binding conformation of the top affinity ligands against macromolecules, by docking experiment.

Methods: The virtual screening was conducted by our Virtual Screening by Docking (VSDK) algorithm and procedure. Small molecules were randomly downloaded by ZINC database. For docking experiment, AutoDock 4.2.6 and AutoDock Tool were used.

Results: It took eight to ten hours for the successful virtual screening of the 2778 small compounds retrieved at random from ZINC database. Among histone H2B E76K mutant (HHEM) inhibitors and DNA methyltransferase (DNMT) inhibitors, the first ranked inhibitors were 1H-1,2,4- triazole-3,5-diamine and 2-ethyl-1,3,4-oxadiazole respectively.

Conclusion: As for the molecular structures obtained from virtual screening, most of the top ten HHEM and DNMT inhibitors contained 5-member rings. More than two times in affinity difference between the top and bottom ten compounds would indicate a successful virtual screening experiment. The histogram chart of AutoDock4 runs appeared in the lowest affinity region with two or three hydrogen bonds indicating a reliable conformation docking.