In Silico Identification of JMJD3 Demethylase Inhibitors.

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.

[Gait pattern of patients with hip arthritis]. / Das Gangmuster von Patienten mit Hüftarthrose.

Automatic recording of the kinematic and kinetic gait pattern has so far not been commonly used in the diagnosis of problems affecting the human loco motor apparatus. In recent decades gait analysis has increasingly been applied in the development of endoprostheses and sports shoes and in rehabilitation, especially of patients with neurological diseases. When a gait laboratory is set up, this demands interdisciplinary cooperation, biomechanical knowledge in physicians and (physio-)therapists, and elaboration of treatment plans allowing direct therapeutic exploitation of the gait data. There are determinant factors in gait pattern, which does not vary qualitatively in the sagittal plane (flexion/extension) with sex and age until the age of 70 years. Quantitatively there is a great deal of individual variation, and the diagnosis of a pathologic function in a particular patient can be difficult. A normal reference population was used to determine the gait pattern characteristic for 32 patients with osteoarthritis of the hip on one or on both sides, and the possible significance of the results for physical and surgical therapy is discussed. The main characteristic of this gait pattern ist the limitation of hip extension before toe-off in the late stance phase. One-third of the patients answer compensate with this increased hip flexion at heel strike, which in turn leads to an increased load on the (more severely) affected side. In consequence, the increased load might lead to progression of the osteoarthritis. In the development of endoprostheses it should be borne in mind that the design may influence the gait pattern, producing overloading of the extremity and perhaps reducing the life of the prosthesis.