Elucidation of Fatty Acid Amide Hydrolase Inhibition by Potent α-Ketoheterocycle Derivatives from Monte Carlo Simulations

Abstract

Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of FAAH that produce analgesia in animal models (J. Med. Chem. 2005, 48, 1849-1856; Bioorg. Med. Chem. Lett. 2005, 15, 1423-1428). Key aspects of the structure-activity data are addressed here through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reduced steric interactions in the active site and a lower torsional energy penalty upon binding.

Correlation of inhibitor effects on enzyme activity and thermal stability for the integral membrane protein fatty acid amide hydrolase

“…Monte Carlo simulations suggest that there are other candidates available for such hydrogen-bond formation. 18 In conclusion this study shows a correlation between inhibitory potency and stabilizing potential of a class of FAAH inhibitors that bear a variety of hydrophilic head groups that are poised to interact with the catalytic triad and cytosolic port of the enzyme. In contrast, when the head group is held constant and a variety of hydrophobic tail groups are examined there is no clear correlation.…”

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

“…Recently, some 3-morpholinomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thiones B ( Figure 1) were found to possess potent cytotoxicity against human cancer cell lines 29 . Moreover, 1,3,4-oxadiazoles are very good bioisosteres of amides and esters, which can contribute substantially in enhancing pharmacological activity by participating in hydrogen bonding interactions with the receptors 30 . In view of the utility of thiosemicarbazide and 1,3,4-oxadiazole scaffolds for the discovery of novel antitumor agents, we thought of synthesizing a new set of thiosemicarbazides C and 1,3,4-oxadiazoles D (Figure 1) to be evaluated in our laboratory for their antitumor activity against breast cancer cells.…”

Design, Synthesis, and Antitumor Activity of Novel 5-Pyridyl-1,3,4-oxadiazole Derivatives against the Breast Cancer Cell Line MCF-7

“…[1][2][3][4][5][6][7][8][9] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase (PTK) that exists on the cell surface and activated by binding to its specific ligands. Mutations involving EGFR could lead to its constant activation, which resulted in uncontrolled cell division.…”