Journal Club: Virtual Screening to ID Novel MLL Inhibitors

October 28, 2016

Today in Journal Club the Fourches Lab discussed the recent publication by Xu et al. that used virtual screening to identify novel inhibitors of the menin-mixed lineage leukemia (MLL) protein. 


Why Target MLL?

  • Protein-protein interactions between menin and MLL may induce MLL translocation resulting in leukemia

  • Identifying an inhibitor to block menin-MLL interactions may prevent this translocation process.


Method Summary

  • Using 74 menin-MLL inhibitors available in the literature Xu et al. were able to develop a molecular docking and pharmacophore 3D-QSAR models to forecast MLL inhibition. 

  • Xu et al. performed fluorescence polarization (FP) and surface plasmon resonance (SPR) binding assays to determine activities of inhibitors identified from virtual screening.


Results Summary

  • Molecular docking and 3D-QSAR were used to screen 180K compounds from the Specs database

  • These virtual screening results identified 121 structurally diverse potentially active compounds that were purchased and tested for MLL inhibition.

  • Five new chemical scaffolds were identified with micro-molar inhibition of MLL 


Fourches Lab Conversation

  • We found the work performed by Xu et al. to be an excellent example of how Cheminformatics can be used to help streamline the drug discovery pipeline. This work demonstrated the full pipeline from in silico studies to in vitro assays.

  • The comparison of non-constrained and constrained GLIDE docking performed by Xu et al. lead to a reflection upon how/when to use non-constrained vs constrained docking approaches within our own research.  


(1) Xu, Y.; Yue, L.; Wang, Y.; Xing, J.; Chen, Z.; Shi, Z.; Liu, R.; Liu, Y.-C.; Luo, X.; Jiang, H.; Chen, K.; Luo, C.; Zheng, M. Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening. J. Chem. Inf. Model. 2016, 56 (9), 1847–1855.

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