Recent investigations show that brain tumor stem-cells (BTSC) might play a plausible role in high recurrence and metastasis in Glioblastoma (GBM). Maternal embryonic leucine zipper kinase (MELK) has been found to be involved in the BTSC proliferation and thus has been identified as a putative molecular drug target for GBM. We modeled 16 ligand induced conformational states of MELK utilizing the available inhibitor data in order to approximate protein flexibility in structure-based virtual screening. A few of the conformations in an ensemble virtual screening protocol showed notable enrichment in recovering the active compounds when seeded with five published decoy sets.  We were able to improve the enrichment by ensemble docking in comparison to single rigid receptor docking. Our investigations also identified several putative binding modes and interactions of known inhibitors to MELK. These results may be utilized to discover novel chemotypes for MELK inhibition and thus the development of therapy targeting BTSC.

Comparative modeling of maternal embryonic leucine zipper kinase inhibitor induced conformational ensembles: Improved structure-based virtual screen enrichment by incorporating protein flexibility

242nd National Meeting (2011)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.