Bioisosteric Replacement for Drug Discovery Supported by the SwissBioisostere Database

Bioisosteric replacement is the strategy of applying chemical modifications to compounds with the goal of improving one or several sub-optimal properties while maintaining the bioactivity at least at the same level. This approach is deeply rooted in medicinal chemistry practice and routinely followed for drug discovery. This chapter describes in detail the content of SwissBioisostere, a specialized database of more than 25 million unique molecular replacements from 65 million occurrence examples obtained from literature and other highly curated data. Several analyses and use-cases are provided that are directly applicable to hit finding or lead optimization to show for example how to replace unwanted chemical groups, how to optimize passive absorption or diffusion across the blood–brain barrier, and how to reduce molecular flexibility or aromaticity. This will help the readers seize the support they can expect from the free and easy access to the database through its web interface (www.swissbioisostere.ch).