Homeyer N, van Deursen R, Ochoa-Montaño B, Heikamp K, Ray P, Zuccotto F, Blundell T, Gilbert I.
Many drug discovery programmes, particularly for infectious diseases, are conducted phenotypically. Identifying the targets of phenotypic screening hits experimentally is complex, time-consuming, and expensive. However, it would be valuable to know what the molecular target(s) is, as knowledge of the binding pose of the hit molecule in the binding site can facilitate the compound optimisation. Furthermore, knowing the target would allow de-prioritisation of less attractive chemical series or molecular targets. To generate target-hypotheses for phenotypic active compounds, an in silico platform was developed that utilises both ligand and protein-structure information to generate a ranked set of predicted molecular targets. As a result of the web-based workflow the user obtains a set of 3D structures of the predicted targets with the active molecule bound. The platform was exemplified using Mycobacterium tuberculosis (M. tb.), the causative organism of tuberculosis. In a test that we performed, the platform was able to predict the targets of 60% of compounds investigated, where there was some similarity to a ligand in the protein database.