The Hedgehog (Hh) signaling pathway has become an important regulator of tissue patterning, stem cell maintenance and cancer growth. In cancer cells, binding of the Hh protein to the membrane receptor patched 1 (PTCH) releases its inhibitory effect on Smo. Activated Smo further transduces downstream cascades to activate the glioma-associated oncogene (GLI) family of transcription factors Recent papers reported that GLI has been considered as a promising target for selective cancer therapy. We have previously isolated numerous naturally occurring GLI inhibitors from plants either using bioassay-guided separation or a new fast isolation method utilizing a GLI-GST immobilized on magnetic dynabeads.<br/><br/>In this research, we selected plants with known anticancer activity and performed<i> in silico</i> screening with 27 alkaloids, 28 lignans and 23 flavonoids against 2GLI as a target. The docking protocols used PLANTS (Protein-Ligand Ant System) software and evaluated parameters were included the interaction energy and hydrogen bond. A crystal structure of cyclopamine binds to 2GLI was used as the reference structure at the score of root mean square deviation of 1.614 Ǻ. As a result, evodiamine and saurosporinone from alkaloid groups; 4-ketopinoresinol and taxiresinol from lignan groups; and xanthohumol from flavonoid groups share similar interactions with protein residues within the 2GLI binding pocket and have potential to inhibit GLI binding.

Docking studies to develop GLI-associated oncogene inhibitors from natural products

249th National Meeting (2015)

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