Lecture series FRIAS Research Focus Chemical Epigenetics 2017 - Wolfgang Sippl

Speaker: Prof. Dr. Wolfgang Sippl, Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg

Topic: Virtual screening and structure-based optimization of epigenetic inhibitors

A variety of structure- and ligand-based techniques for automated virtual library screening has been developed over the last decade. Pharmacophore and ligand docking methods are often applied in a hierarchical manner in order to reduce the number of potential hits from millions of compounds to a small subset of manageable size. The growing number of successful virtual screening studies has shown the potential of this approach. However, often virtual screening is resulting in weakly active hits, promiscuous binders or pan assay interfering compounds. Thus, knowledge-based approaches as well as binding free energy calculations have been developed to increase the accuracy and performance of in silico screening campaigns. In the present work the structure-based optimization of novel inhibitors for several histone modifying enzymes and readers is presented. With the usage of X-ray crystallography, molecular docking and binding free energy calculations nanomolar inhibitors could be obtained. The advantages as well as the drawbacks of virtual screening and binding free energy calculation will be discussed.