A Data-Driven Perspective on Bioisostere Evaluation: Mapping the Benzene Bioisostere Landscape with BioSTAR.

The bioisostere landscape is continually expanding, with new scaffolds emerging as alternatives in drug design. Increasingly, medicinal chemists face the challenge of selecting and prioritising these bioisosteres, often relying on personal experience and anecdotal evidence. In this Perspective, we lay out a data-driven approach to analyze the bioisostere landscape, using benzene bioisosteres as a representative example, and quantitatively compare replacements based on their impact on bioactivity, solubility, and metabolic stability. To support the findings of the analysis, we highlight recent and particularly elegant examples of benzene bioisostere applications while identifying areas where further development could significantly benefit the community. By providing this Perspective and associated data-mining workflow (BioSTAR), we aim to support more informed decision-making in bioisosteric replacement selection in drug design and inspire future innovations in bioisostere design.