Exploring isofunctional molecules: Design of a benchmark and evaluation of prediction performance.

Identification of novel chemotypes with biological activity similar to a known active molecule is an important challenge in drug discovery called 'scaffold hopping'. Small-, medium-, and large-step scaffold hopping efforts may lead to increasing degrees of chemical structure novelty with respect to the parent compound. In the present paper, we focus on the problem of large-step scaffold hopping. We assembled a high quality and well characterized dataset of scaffold hopping examples comprising pairs of active molecules and including a variety of protein targets. This dataset was used to build a benchmark corresponding to the setting of real-life applications: one active molecule is known, and the second active is searched among a set of decoys chosen in a way to avoid statistical bias. This allowed us to evaluate the performance of computational methods for solving large-step scaffold hopping problems. In particular, we assessed how difficult these problems are, particularly for classical 2D and 3D ligand-based methods. We also showed that a machine-learning chemogenomic algorithm outperforms classical methods and we provided some useful hints for future improvements.