Hit Identification Against DNA Topoisomerases Using Virtual Screenings

Abstract

Hit Identification Against DNA Topoisomerases Using Virtual ScreeningsAtilla AkdemirComputer-aided drug discovery laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkeyaakdemir@bezmialem.edu.tr DNA is in a supercoiled and compact state in non-dividing cells. However, DNA must be unwound to enable replication and transcription by DNA polymerases and RNA polymerases, respectively. The winding and unwinding of DNA is being performed by DNA topoisomerases and as such these enzymes are crucial in cell division and cell growth. Therefore, DNA topoisomerase inhibitors are clinically used in cancer chemotherapy, as antiviral agents and as antibiotics. Human DNA topoisomerase II isoforms α and β are targets for several chemotherapeutic agents such as etoposide. Here we aim to identify structurally new inhibitors of these enzymes by virtual screening procedures. To this end, a small virtual library has been constructed and this library has subsequently been docked into the active sites of isoforms α and β. Compounds that were expected to inhibit the enzymes were synthesized and subsequently tested in enzyme inhibition assays.