As transcriptional factors are the current area of concern in novel anticancer drug designing, this study was designed to develop a suitable drug (lead) molecule to block the DNA-binding site of cancer-causing E2F3 transcription factor (overexpressed in prostate, lung, bladder cancers) by using computer-aided drug design approach and implementing homology modeling, molecular docking and virtual high-throughput screening techniques. A reasonable 3-dimensional structure model of E2F3 transcription factor was generated by following homology modeling technique and using SWISS-MODEL server. The stereochemical evaluation of the generated model was carried out by using the program PROCHECK. The active site residues of the DNA-binding domain that make critical contacts within the major groove of DNA were determined by analyzing the crystal structure of the template (E2F4). Then, by using this structure model a chemical database (containing 3D structures of available chemical compounds) ZINC was virtually screened: only those molecules having molecular weight between 300 to 350, neutral charge, hydrogen bond donors 0/1, hydrogen bond acceptors 3/5, rotatable bonds 2/7 and a value of xLogP between -2 and 4, were taken into account. The compounds yielded by this database filtration step were then subjected to 10 run docking studies with the program AutoDock 4.02 to search for the suitable hits. This step resulted in 31 hits. From
these hits the compounds with binding energy lower than -3.5 Kcal/mol and showing maximum hydrogen bonding interaction with active site were further selected. This step returned 6 compounds which were further evaluated by giving 30 runs of docking in the sense to improve the interaction with the active site residues (hydrogen bonding) and binding energy. 3 compounds with binding energy less than - 4.0 Kcal/mol were further subjected to visual inspection in order to evaluate their binding poses at the active site. One was eliminated and the remaining two were further subject to 50 docking runs see any improvement in ener4gy. One of the them showed a little improvement in biding energy, however, both were suggested as suitable ,leads, as the difference in their binding energies was very small and both were making equal number of hydrogen bonds with the DNA binding site of target F2F3