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Papers of the Week

Papers: 24 Dec 2022 - 30 Dec 2022

2022 Dec 07

Int J Mol Sci



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


Morgillo C M, Lupia A, Deplano A, Pirone L, Fiorillo B, Pedone E, Luque JF, Onnis V, Moraca F, Catalanotti B
Int J Mol Sci. 2022 Dec 07; 23(24).
PMID: 36555144.


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.