Download MendeleyIn Silico Identification of JMJD3 Demethylase Inhibitors.
Esposito, C., Wiedmer, L., Caflisch, A.(2018) J Chem Inf Model 58: 2151-2163
- PubMed: 30226987
- DOI: https://doi.org/10.1021/acs.jcim.8b00539
- Primary Citation of Related Structures:
6FUK, 6FUL, 6G8F - PubMed Abstract:
In the search for new demethylase inhibitors, we have developed a multistep protocol for in silico screening. Millions of poses generated by high-throughput docking or a 3D-pharmacophore search are first minimized by a classical force field and then filtered by semiempirical quantum mechanical calculations of the interaction energy with a selected set of functional groups in the binding site. The final ranking includes solvation effects which are evaluated in the continuum dielectric approximation (finite-difference Poisson equation). Application of the multistep protocol to JMJD3 jumonji demethylase has resulted in a dozen low-micromolar inhibitors belonging to five different chemical classes. We have solved the crystal structure of JMJD3 inhibitor 8 in the complex with UTX (a demethylase in the same subfamily as JMJD3) which validates the predicted binding mode. Compound 8 is a promising candidate for future optimization as it has a favorable ligand efficiency of 0.32 kcal/mol per nonhydrogen atom.
Organizational Affiliation:
Department of Biochemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland.
