In silico identification of JMJD3 demethylase inhibitors

TitleIn silico identification of JMJD3 demethylase inhibitors
Publication TypeJournal Article
Year of Publication2018
AuthorsEsposito C., Wiedmer L., Caflisch A.
JournalJournal of Chemical Information and Modeling
Date Published2018 Sep 18
Type of ArticleResearch Article
ISSN1549-960X
Abstract

In the search for new demethylase inhibitors we have developed a multi-step protocol for in silico screening. Millions of poses generated by high-throughput docking or 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 multi-step protocol to the JMJD3 jumonji demethylase has resulted in a dozen low-micromolar inhibitors belonging to five different chemical classes. We have solved the crystal structure of the JMJD3 inhibitor 8 in the complex with UTX (a demethylase in the same sub-family 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 non-hydrogen atom.

DOI10.1021/acs.jcim.8b00539
pubindex

0241

Alternate JournalJ. Chem. Inf. Model.
PubMed ID30226987
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