Abstract 2673: In silico design of E2F1 mimics as potential anticancer agents

Abstract

Introduction. We report the construction of a homology model of the human E2F1-DP1 transcription factor complex with DNA to be used as a tool for design of drugs targeted to the promoter of this oncogene based on interference of transcription factor binding. Using shape-based docking and force field calculations, we investigate the development of novel penetratin-based (PED) peptides, obtained by phage display, (E2F1 mimics) as potential binders to the major groove of GC-rich regions of DNA. Computational Procedures. The homology model of E2F1-DP1 complex with DNA was built using the Modeller (9v5) program. We used the DNA binding domains of the E2F1 and DP1 sequences (NCBI accession #'s AAC50719 and NP009042 respectively), and the x-ray crystal structure of the E2F4-DP2 complex with DNA (1CF7.pdb) as the primary template. The DNA from the crystal structure was modeled in place using the default spatial constraints in Modeller. The PED based peptide models were built using the x-ray crystal structure of the antennapedia homeodomain-DNA complex (9ANT.pdb) as a template. The alignment is shown below (The penetratin portion is shown in bold and the variable portion is in italics.). _aln.pos 10 20 30 40 50 60 9antA RQTYTRYQTLELEKEFHFNRYLTRRRRIEIAHALSLTERQIKIWFQNRRMKWKK—–EN brt1 ————————————–RQIKIWFQNRRMKWKKHHHRLSH _consrvd **************** The PatchDock program was used to dock the peptides to the DNA structure from 1CF7.pdb based on shape complementarity. The best shape scoring major-groove binding orientation was selected and refined via energy minimization using the Amber ff99SB force field. Interaction energy scores were computed from the non-bonded energy terms of the Amber force field (Eint = ∑ Evdw + ∑ Eelec). Data Summary. The HHHRLSH sequence is predicted to form a more stable complex compared to the GGGALSA sequence. The PED-HHHRLSH peptide was shown to have potent activity against several cancer cell lines (Xie, et al. AACR 2009). In the case of the HHHRLSH sequence, the model predicts enhanced stability in going from L-Arg (−646.0 kcal/mol) to D-Arg (−688.0 kcal/mol). Conclusions. The α3 helix of E2F1 composed of KRRIYDITNVLEGI binds to the major groove of GC-rich DNA. The PED-HHHRLSH peptide complex with DNA (−646.0 kcal/mol) has similar interaction energy to that of the E2F1-DNA complex (−653.0 kcal/mol), is a stable α-helical structure, and is a potential E2F1 mimic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2673.