A Molecular Representation to Identify Isofunctional Molecules

Abstract

The challenges of drug discovery from hit identification to clinical development sometimes involves addressing scaffold hopping issues, in order to optimise molecular biological activity or ADME properties, or mitigate toxicology concerns of a drug candidate. Docking is usually viewed as the method of choice for identification of isofunctional molecules, i. e. highly dissimilar molecules that share common binding modes with a protein target. However, the structure of the protein may not be suitable for docking because of a low resolution, or may even be unknown. This problem is frequently encountered in the case of membrane proteins, although they constitute an important category of the druggable proteome. In such cases, ligand‐based approaches offer promise but are often inadequate to handle large‐step scaffold hopping, because they usually rely on molecular structure. Therefore, we propose the Interaction Fingerprints Profile (IFPP), a molecular representation that captures molecules binding modes based on docking experiments against a panel of diverse high‐quality proteins structures. Evaluation on the LH benchmark demonstrates the interest of IFPP for identification of isofunctional molecules. Nevertheless, computation of IFPPs is expensive, which limits its scalability for screening very large molecular libraries. We propose to overcome this limitation by leveraging Metric Learning approaches, allowing fast estimation of molecules IFPP similarities, thus providing an efficient pre‐screening strategy that in applicable to very large molecular libraries. Overall, our results suggest that IFPP provides an interesting and complementary tool alongside existing methods, in order to address challenging scaffold hopping problems effectively in drug discovery.