In Silico Identification of JMJD3 Demethylase Inhibitors

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.

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

“…JmjC histone demethylases have emerged as promising drug targets, ,− with inhibitor discovery programs being reported by us − and others, − as recently reviewed. ,,− A majority of reported JmjC KDM inhibitors function by active site metal chelation and competitive displacement of the co-substrate 2OG. − Very recently, covalent KDM5 inhibitors , and inhibitors of both the lysyl- and arginyl-demethylase activities have also been reported.…”

SQM/COSMO Scoring Function: Reliable Quantum‐Mechanical Tool for Sampling and Ranking in Structure‐Based Drug Design

“…The authors successfully applied the approach at PM6 level to high-throughput virtual screening of 2.7 million of tyrosine kinase ligands [62a] and more recently also at PM7 level in search of new demethylase inhibitors. [63] Overall, the results of the above-mentioned SQM-based approaches are very promising in terms of predictive power, however there is also potential room for further improvement, e. g. in addressing different sources of errors, in conformational sampling and protein flexibility, in solvation and entropic contributions or in hardware and software acceleration.…”

“…The SQM‐based pairwise‐additive approach introduced by Zhou and Caflisch [62a] combines extensive docking, MM‐minimization and rescoring of the pose with selected binding site residues represented as probes, i. e. minimal models. The authors successfully applied the approach at PM6 level to high‐throughput virtual screening of 2.7 million of tyrosine kinase ligands [62a] and more recently also at PM7 level in search of new demethylase inhibitors [63] …”

Synthesis, Biological Evaluation and In Silico Investigation of Novel Functionalized Imidazole-Based KDM6 Inhibitors

“…The design idea for the proposed imidazole-based KDM6 inhibitors was inspired by structural determinants of previously reported inhibitors of KDM6 with introduced modifications to explore the possible medicinal chemistry space of such inhibitors [13,[17][18][19]. Such inhibitors act through a competitive mechanism with the co-factor α-ketoglutaric acid [13].…”

“…The ethyl ester prodrug of this compound, has been used to characterize and establish the biochemical role of KDM6 in many disease states [14][15][16]. Very few research projects were conducted to further investigate the medicinal chemistry space of KDM6 inhibitors and further characterize the structureactivity relationship features of inhibitory agents [17][18][19]. In this work, we introduce a novel medicinal chemistry design of chemical entities with potential KDM6 inhibitory activities.…”