With the ever-increasing number of synthesis-on-demand compounds for drug lead discovery, there is a great need for efficient search technologies. We present the successful application of a virtual screening method that combines two advances: (1) it avoids full library enumeration (2) products are evaluated by molecular docking, leveraging protein structural information. Crucially, these advances enable a structure-based technique that can efficiently explore libraries with billions of molecules and beyond. We apply this method to identify inhibitors of ROCK1 from almost one billion commercially available compounds. Out of 69 purchased compounds, 27 (39%) have K_i values < 10 µM. X-ray structures of two leads confirm their docked poses. This approach to docking scales roughly with the number of reagents that span a chemical space and is therefore multiple orders of magnitude faster than traditional docking.

The nuclear farnesoid X receptor (FXR) is a ligand activated transcription factor and acts as cellular sensor for bile acids. In this role, FXR is a highly important liver protector and FXR inhibition by antagonists or knockout has shown several deleterious effects. A recent report characterized non-steroidal anti-rheumatic drugs (NSAIDs) such as ibuprofen or diclofenac as FXR antagonists and linked hepatotoxic effects of these drugs with antagonistic activity on FXR. Since this would guide a way to develop safer anti-inflammatory agents by sparing FXR, we intended to further characterize the reported antagonistic activity and intensively investigated ibuprofen, indometacin and diclofenac. However, we conclude that these agents do not interact with FXR and that the reported reduced FXR signaling induced by CDCA in presence of NSAIDs is merely a consequence than a cause of hepatotoxicity.