Application of a FLAP-Consensus Docking Mixed Strategy for the Identification of New FAAH Inhibitors.

FAAH is the principal responsible for the termination of anandamide signaling, a major actor of the endocannabinoid system. The indirect stimulation of endocannabinoid responses achieved through FAAH inhibition can represent a valid pharmacological strategy for the treatment of neurodegenerative and neuroinflammatory diseases such as multiple sclerosis, Alzheimer’s, Huntington’s, and Parkinson’s diseases, as well as rheumatoid arthritis, gastrointestinal inflammatory states, anxiety and other pathologies. With the aim of identifying new non-covalent FAAH inhibitors and also experimentally validating the reliability of the recently reported consensus docking approach, we filtered a commercial database of about 1 million compounds by using a mixed FLAP/consensus docking approach. Enzymatic assays showed FAAH inhibitory activity and selectivity versus MAGL for 8 out of the 10 top ranked compounds, with IC50 values in the low micromolar range for the two most active compounds. These results demonstrate the reliability of the virtual screening strategy and constitute an experimental validation of the consensus docking approach. Moreover, the two most active compounds described could represent promising leads for the development of high potent non-covalent FAAH inhibitors.