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.