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.