Manoalide：结构活性研究和磷脂酶A2失活的药效基团的定义。,Molecular Pharmacology

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Manoalide：结构活性研究和磷脂酶A2失活的药效基团的定义。
Molecular Pharmacology ( IF 3.2 ) Pub Date : 1989-11-01
K B Glaser ₁ , M S de Carvalho , R S Jacobs , M R Kernan , D J Faulkner

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Manoalide是有效的抗炎海洋天然产物，是蛇毒磷脂酶A2（PLA2; EC 3.1.1.4）的直接灭活剂。已经显示，Manoalide具有不可逆地抑制PLA2的作用，并具有选择性修饰赖氨酸残基的数量。灭活的机理尚未阐明，因此进行了结构-活性关系研究，以确定结合在γ-羟基丁烯内酯，α-羟基二氢吡喃和三甲基环己烯基环系统中的各种官能团对功效的影响（不可逆性）和该系列抑制剂的效力。这些研究表明1）不可逆结合的Manoalide需要在α-羟基二氢吡喃环中存在半缩醛，2）γ-羟基丁烯内酯环参与了Manoalide与PLA2的初始相互作用，并且3）三甲基环己烯基环系统的疏水性质允许Manoalide与PLA2之间的非键合相互作用增强了这些类似物的效力。这些结构-活性关系研究表明，甘露糖化物的闭环形式是占主导地位的分子种类，其解释了甘露糖化物对PLA2的选择性和有效抑制。机理的阐明有待在模型系统中和使用PLA2对甘露聚糖（类似物）-蛋白质加合物的结构进行进一步的详细物理化学研究。这些结构-活性关系研究表明，甘露糖化物的闭环形式是占主导地位的分子种类，其解释了甘露糖化物对PLA2的选择性和有效抑制。机理的阐明有待在模型系统中和使用PLA2对甘露聚糖（类似物）-蛋白质加合物的结构进行进一步的详细物理化学研究。这些结构-活性关系研究表明，甘露糖化物的闭环形式是占主导地位的分子种类，其解释了甘露糖化物对PLA2的选择性和有效抑制。机理的阐明有待在模型系统中和使用PLA2对甘露聚糖（类似物）-蛋白质加合物的结构进行进一步的详细物理化学研究。

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Manoalide: structure-activity studies and definition of the pharmacophore for phospholipase A2 inactivation.

Manoalide is a potent antiinflammatory marine natural product and a direct inactivator of venom phospholipase A2 (PLA2; EC 3.1.1.4). Manoalide has been shown to irreversibly inhibit PLA2, with the corresponding modification of a selective number of lysine residues. The mechanism of inactivation has not yet been elucidated and structure-activity relationship studies were, therefore, performed in order to determine the contributions of the various functional groups incorporated in the gamma-hydroxybutenolide, alpha-hydroxydihydropyran, and trimethylcyclohexenyl ring systems to the efficacy (irreversibility) and potency of this series of inhibitors. These studies indicate that 1) the presence of the hemiacetal in the alpha-hydroxydihydropyran ring is required for irreversible binding of manoalide, 2) the gamma-hydroxybutenolide ring is involved in the initial interaction of manoalide with PLA2, and 3) the hydrophobic nature of the trimethylcyclohexenyl ring system allows nonbonded interactions between manoalide and PLA2 that enhance the potency of these analogs. These structure-activity relationship studies suggest that the closed ring form of manoalide is the predominant molecular species that accounts for the selective and potent inhibition of PLA2 by manoalide. Elucidation of the mechanism awaits further detailed physicochemical studies on the structure of the manoalide (analog)-protein adducts in model systems and using PLA2.

更新日期：2019-11-01

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