Application of a FLAP-consensus docking mixed strategy for the identification of new fatty acid amide hydrolase inhibitors.
Fatty acid amide hydrolase (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 noncovalent 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 (fingerprints for ligands and proteins) 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 noncovalent FAAH inhibitors.
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Giulio
G
Poli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Niccolò
N
Giuntini
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Adriano
A
Martinelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Tiziano
T
Tuccinardi
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases