In an early definition by Walters, Stahl, and Murcko , virtual screening (VS) is described as the “Use of high-performance computing to analyze large databases of chemical compounds in order to identify possible drug candidates.”
Virtual screening has become an integral part of the drug discovery process. It has largely been a numbers game focusing on questions like how can we filter down the enormous chemical space of over 1060 conceivable compounds to a manageable number that can be synthesized or purchased and tested. Although filtering the entire chemical universe might be a fascinating question, more practical VS scenarios focus on designing and optimizing targeted combinatorial libraries and enriching libraries of available compounds from in-house compound repositories or vendor offerings.
The purpose of virtual screening is to come up with hits of novel chemical structure that bind to the macromolecular target of interest. Thus, success of a virtual screen is defined in terms of finding interesting new scaffolds rather than many hits. Interpretations of VS accuracy should therefore be considered with caution. Low hit rates of interesting scaffolds are clearly preferable over high hit rates of already known scaffolds.
In a logical and didactic way, this volume is organized in four parts covering principles, challenges, practical guidelines, and case studies under different scenarios. Chapters of Part One are dedicated to virtual screening of chemical space, processing of small molecule databases for virtual screening, ligand-based and target-based virtual screening, virtual screening with 3D pharmacophore models, and docking methods. Challenges discussed in Part Two comprise affinity prediction, fragment-based approaches, handling of protein flexibility, as well as consideration of water and solvation effects, as well as parallel virtual screening for compound profiling and prediction of off-target effects. Finally, strategies, recommendations, and caveats for applying virtual screening methodology are given and many success stories are described.
As an add-on value, this volume contains two appendices. A brief tabular compilation, including classification, short description, references, and links, gives a very informative software overview. Beyond it, successful virtual screening application studies for pharmacological targets are tabulated.
We are very grateful to Christoph Sotriffer who assembled a team of leading experts to discuss all above-mentioned aspects. This book is well suited both for all practitioners in medicinal chemistry and for graduate students who want to learn how to apply virtual screening methodology. We are also grateful to Frank Weinreich and Nicola Oberbeckmann-Winter for their ongoing support and enthusiasm for our series “Methods and Principles in Medicinal Chemistry.”
Raimund Mannhold, Düsseldorf
Hugo Kubinyi, Weisenheim am Sand
Gerd Folkers, Zürich