Introduction/Objective: Fatty acid amide hydrolase (FAAH) is a membrane-bound homodimeric enzyme of the endocannabinoid system that hydrolyzes active endocannabinoids to inactive metabolites and as such represents a lucrative target for the development of FAAH inhibitors for the treatment of pain, anxiety, and other CNS-related conditions. Phenolic compounds found in nutmeg (Myristica fragrans) have recently been identified that inhibit human FAAH (hFAAH) and represent lead compounds for the development of such therapeutic agents. Here, we used molecular modeling techniques to generate hypotheses about the mechanistic details regarding inhibition of hFAAH by these phenolic compounds.
Methods/Study Design: Freely-available software tools were used for all stages of the modeling study. Avogadro 1.2.0 was used to generate 3D molecular models of the phenolic nutmeg lead compounds. Experimentally-determined FAAH structures were retrieved from the Protein Data Bank (PDB). ClustalX 2.1 and MEGA 11 were used to align the primary amino acid sequences of rat and human FAAH, and homology models of human FAAH were generated with MODELLER 10.4. SwissDock was then used to obtain docked solutions for the lead compounds. Docked solutions were analyzed and visualized using Chimera 1.16 and PyMOL 2.5.
Results: Several energetically-favorable clusters of docked solutions were identified for each of the three lead compounds licarin A, 5’-methoxylicarin A, and malabaricone C, highlighting probable binding sites for these compounds. The docked solutions exhibited varying degrees of complementarity based on shape and electrostatic properties. Non-covalent protein–ligand interactions were identified.
Conclusion: The results and knowledge gained from this study have allowed us to 1) propose a plausible structure-based mechanism of FAAH inhibition by the lead compounds and 2) identify and/or design analogs of the lead compounds with potentially enhanced hFAAH affinity and inhibitory activity.

Ehab Abourashed

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