A Real-World Perspective on Molecular Design

Bernd Kuhn, Wolfgang Guba, Jérôme Hert, David Banner, Caterina Bissantz, Simona Ceccarelli, Wolfgang Haap, Matthias Körner, Andreas Kuglstatter, Christian Lerner, Patrizio Mattei, Werner Neidhart, Emmanuel Pinard, Markus G. Rudolph, Tanja Schulz-Gasch, Thomas Woltering, Martin Stahl

We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate pre-processing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements that enable chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.