Integrated Fragment-Based Approaches on the Route to Novel IDO1 Modulators

Fragment-based approaches (FBDD) are emerging as an innovative rational strategy in drug discovery to efficiently explore the diversity of the chemical space, focusing on few high-quality hit compounds rather than large numbers of lead compounds.[1] Specifically, these approaches rely on the paradigm that a small collection of sufficiently differentiated small molecular weight compounds (MW < 300 Da) is able to sample a larger portion of the chemical space than a complex library composed of relatively larger molecules. To be undertaken, these approaches require the implementation of computational techniques as well as biophysical methods into classical pharmacological assays. In this communication, we will report the results of an FBDD strategy applied to disclose novel modulators of IDO1, a validated druggable target for cancer diseases.[2] In particular, the first step of the adopted FBDD strategy consisted in the molecular docking of a small collection of diverse fragments (56.000 cpds) into the crystal structure of IDO1.[3] Then, NMR screening based on WATER LOGSY approach was applied to selected virtual hits in order to confirm true ligand binders from NOT binders. Microscale thermophoresis analysis (MST) was used to further discriminate ligand binders endowed with protein site-specific interactions from those endowed with protein surface-not specific interactions. Finally, cell-based pharmacological assays were applied to confirm the target modulation properties of confirmed site-specific ligand binders.