Abstract 1661: Molecular modeling of an emerging chemopreventive agent wedelolactone against multiple targets in oncogenetic pathway
Authors: sadia sarwar, Tauqeer Ahmed, Jun Q. Yu, Fazlul Huq
Journal: Cancer Research (2019)

Abstract Targeting multiple pathways involved either in drug resistance or/and in intact cancer cell survival are promising strategies. Epigenetics is being immensely recognized as exciting frontier in cancer research. Kinases have direct and indirect epigenetic impacts. Kinases are among the popular discovery targets and kinase inhibitors represent one of the key classes of drugs in the last two decades of oncology research. Braf kinases and cyclin dependent protein kinases exert their role as key mediators of signal transduction, apoptosis and overall intercellular communications. Topoisomerase II inhibitors including etoposide, tinoposide are important drugs used in breast cancer, sarcomas and lymphomas while inhibitors of dihydrofolatereductase, a key enzyme in the synthesis of DNA, are also clinically useful antagonists/inhibitors of ERα and aromatases have the potential to be therapeutically significant towards estrogen mediated breast, ovarian and uterine (endometrium) cancers. Wedelolactone is emerging as a small molecule with cytotoxic potential. Auto Dock Vina program was used for docking study .Affinity of best docked pose of ligand and protein target complex was determined by E-value (Kcal/mol).3D-structures of target proteins were taken from http://www.rcsb.org/pdb/home/home.do. The target proteins include dihydrofolatereductase, braf kinase, cyclin dependent protein kinase, nuclear factor kappa b, topoisomerase II, aromatase, estrogen receptor alpha and alkaline phosphatase (PDB ID: 2C2T, PDB ID: 3Q4C, PDB ID: 1HCL, PDB ID: 1NFK, PDB ID: 5B58, PDB ID: 3S7S, PDB ID: 3ERT, PDB ID: 1ANI). The structures (wedelolactone and standard drugs) were downloaded in.xml format and converted to PDB format via Open Babel JUI software. PDB form of wedelolactone, EGCG, reference drugs and target proteins were converted to PDBQT via AutoDock Tools (Version1.5.6 Sep_17_14). Discovery studio visualizer was used for post docking interactions for number of Hydrogen bonds (classical and non-classical), π-π bonds and other hydrophobic interactions by binding amino acid residues. The cell survival fraction was determined using the MTT reduction assay. The order of binding affinity of wedelolactone was found as: estrogen receptor alpha &amp;gt;dihydrofolate reductase&amp;gt;braf kinase &amp;gt; topoisomerase II &amp;gt; CDPK &amp;gt; aromatase &amp;gt; alkaline phosphatase &amp;gt;Nfkb. We identified wedelolactone as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in oncogenic as depicted through its In-silico study. Further research should be encouraged to investigate different aspects of wedelolactone. Note: This abstract was not presented at the meeting. Citation Format: sadia sarwar, Tauqeer Ahmed, Jun Q. Yu, Fazlul Huq. Molecular modeling of an emerging chemopreventive agent wedelolactone against multiple targets in oncogenetic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1661.