Application of a FLAP-consensus docking mixed strategy for the identification of new fatty acid amide hydrolase inhibitors

Journal of Chemical Information and Modeling
Giulio PoliTiziano Tuccinardi

Abstract

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 compoun...Continue Reading

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Citations

May 20, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Carlotta GranchiTiziano Tuccinardi
Aug 27, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Giulio PoliTiziano Tuccinardi
Jun 18, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Giulio PoliTiziano Tuccinardi
Sep 25, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Carlotta GranchiTiziano Tuccinardi
Jun 26, 2018·International Journal of Molecular Sciences·Giulio PoliTiziano Tuccinardi
May 12, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Giulio PoliTiziano Tuccinardi
Jan 31, 2019·Journal of Cellular Physiology·Concetta Russo SpenaFlavio Rizzolio
Jan 31, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Giulio PoliCarlotta Granchi
Apr 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Giulio PoliTiziano Tuccinardi
Jun 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elena PiniDaniela Barlocco
Feb 6, 2020·Mini Reviews in Medicinal Chemistry·Mayara Dos Santos MaiaMarcus Tullius Scotti
Apr 19, 2019·ACS Medicinal Chemistry Letters·Margherita LapilloFlavio Rizzolio

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