Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations
Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations
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DOI：
10.1021/ja055438j
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发表时间：
2005-12-14
影响因子：
15
通讯作者：
Jorgensen, WL
中科院分区：
文献类型：
--
作者：
Guimaraes, CRW;Boger, DL;Jorgensen, WL
脂肪酸酰胺水解酶（FAAH）是一种丝氨酸水解酶，负责降解内源性大麻素激动剂花生四烯酸和诱导睡眠的脂质油酰胺。最近，Boger及其同事报道了一类在动物模型中产生镇痛作用的FAAH的强效、选择性和有效的可逆α-酮杂环抑制剂（J.Med.Chem.2005，48，1849-1856; Bioorg.医学化学快报2005，15，1423-1428）。结构-活性数据的关键方面在这里解决通过计算分析FAAH抑制使用Monte Carlo（MC）模拟结合自由能微扰（FEP）计算。MC/FEP模拟表明，在2-酮基-恶唑和2-酮基-1，3，4-恶二唑衍生物的C5位置处掺入吡啶通过在吡啶基氮与Lys 142和Thr 236之间形成氢键阵列而显著增强结合亲和力。结果还将恶唑被恶二唑取代后的活性增强归因于活性位点中的空间相互作用减少和结合后的较低扭转能罚分。
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.