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.
