Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition

Morgillo, Carmine Marco;Lupia, Antonio;Deplano, Alessandro;Pirone, Luciano;Fiorillo, Bianca;Pedone, Emilia;Luque, F. Javier;Onnis, Valentina;Moraca, Federica;Catalanotti, Bruno

2022-01-01

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Abstract

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out in our previous work for the most potent inhibitor 2-amino-3-chloropyridine amide (TPA14), we have investigated its non-competitive mechanism of action using molecular dynamics, thermodynamic integration and QM-MM/GBSA calculations. The computational studies highlighted the impact of mutations on the receptor binding pockets and elucidated the molecular basis of the non-competitive inhibition mechanism of TPA14, which prevents the endocannabinoid anandamide (AEA) from reaching its pro-active conformation. Our study provides a rationale for the design of non-competitive potent FAAH inhibitors for the treatment of neuropathic pain and chronic inflammation.