A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents.

Author

Rati Kailash Prasad Tripathi

Affiliation

Department of Pharmaceutical Science, Sushruta School of Medical and Paramedical Sciences, Assam University (A Central University), Silchar, Assam, 788011, India; Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India. Electronic address: [Email]

Abstract

Fatty acid amide hydrolase (FAAH) is an important enzyme creditworthy of hydrolyzing endocannabinoids and related-amidated signalling lipids, discovery of which has pioneered novel arena of pharmacological canvasses to unwrap its curative potency in various diseased circumstances. It presents contemporary basis for understanding molecules regulating and mediating inflammatory reactions, pain, anxiety, depression, and neurodegeneration. FAAH inhibitors form vital approach for discovery of therapeutic agents that are concerned with local elevation of endocannabinoids under certain stimuli, debarring adverse/unwanted secondary effects from global activation of cannabinoid receptors by exogenous cannabimimetics. During past decades, several molecules with excellent potency developed through tailor-made approaches entered into clinical trials, but none could reach market. Hence, hunt for novel, non-toxic and selective FAAH inhibitors are on horizon. This review summarizes present perception on FAAH in conjunction with its structure, mechanism of catalysis and biological functions. It also foregrounds recent development of molecules belonging to diverse chemical classes as potential FAAH inhibitors bobbing up from in-depth chemical, mechanistic and computational studies published since 2015-November 2019, focusing on their potency. This review will assist readers to obtain rationale on FAAH as potential target for addressing various disease conditions, acquiring significant knowledge on recently established inhibitor scaffolds and their development potentials. New technologies including MD-MM simulations and 3D-QSAR studies allow mechanistic characterization of enzyme. Assessment of in-vitro and in-vivo efficacy of existing FAAH inhibitors will facilitate researchers to design novel ligands utilizing modern drug design methods. The discussions will also impose precaution in decision making process, quashing possibility of late stage failure.

Keywords

3D-QSAR studies,Endocannabinoid system,FAAH inhibitors,Fatty acid amide hydrolase (FAAH),Molecular dynamics-molecular mechanics (MD-MM) simulations,Structure-activity relationship,

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