ArticleJournal of medicinal chemistry2011
Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 44 citations in OpenAlex.
- Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations.Journal of chemical information and modeling · 2023Review
- Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency.Journal of chemical information and modeling · 2022Article
- Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors.ACS omega · 2018Article
- The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.ChemMedChem · 2016Article
- Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies.ChemMedChem · 2016Review
- Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets.PLoS computational biology · 2015Article
- Energetically unfavorable amide conformations for N6-acetyllysine side chains in refined protein structures.Proteins · 2013Article
- Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors.Journal of medicinal chemistry · 2013Article
- Identification and characterization of carprofen as a multitarget fatty acid amide hydrolase/cyclooxygenase inhibitor.Journal of medicinal chemistry · 2012Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and potent FAAH inhibitors (FAAHi), there are the cyclic piperidine and piperazine aryl ureas. FAAH hydrolyzes efficiently the amide bond of these compounds, forming a covalent enzyme-inhibitor adduct. To rationalize this experimental evidence, we performed an extensive computational analysis centered on piperidine-based PF750 (1) and piperazine-based JNJ1661010 (2), two potent lead compounds used to generate covalent inhibitors as clinical candidates. We found that FAAH induces a distortion of the amide bond of the piperidine and piperazine aryl ureas. Quantum mechanics/molecular mechanics ΔE(LUMO-HOMO) energies indicate that the observed enzyme-induced distortion of the amide bond favors the formation of a covalent FAAH-inhibitor adduct. These findings could help in the rational structure-based design of novel covalent FAAHi.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.