Ivet, Bahar, Distinguished Professor and John K. Vries Chair

Department of Computational & Systems Biology

School of Medicine, University of Pittsburgh

Target flexibility, druggability and promiscuity: Major considerations in computer-aided drug discovery

Recent years have demonstrated the utility of computational approaches for assisting in accelerating drug discovery and development. However, many targets remain elusive, not all targets are druggable, and many drugs target a multiplicity of proteins. It is widely recognized that accurate prediction of ligand-binding poses and affinity is not possible unless the conformational flexibility of the target protein is also considered, and efficient methods are needed for sampling accessible conformers. Druggability simulations also emerged in recent years as useful first screens for avoiding attrition effects that may arise at later stages of drug development. Finally, numerous studies demonstrate that individual drug-target binding considerations are not sufficient to assess the effects of drugs on a cellular level, and quantitative systems pharmacology methods are developed for rapid assessment of new purposes for old drugs or for predicting potential side effects. A summary of computational methods and tools recently developed to address these issues will be presented.