Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, P.O. Box 180, 10002 Zagreb, Croatia.
Bioorg Chem. 2012 Apr-Jun;41-42:28-34. doi: 10.1016/j.bioorg.2012.01.004. Epub 2012 Jan 24.
A series of novel adamantane-substituted guanylhydrazones was synthesized and used in a study of inhibitory potential toward butyrylcholinesterase. The experimental results were further supported by using docking studies to examine the behavior of the inhibitors within the active site regions of the enzyme. The enzyme-inhibitor dissociation constants K(i) were determined from Hunter-Downs diagrams using Ellman's method for cholinesterase activity determination. Compounds 2-(N-guanidino)iminoadamantane hydrochloride (1) and 2,4-bis(N,N'-guanidino)iminoadamantane dihydrochloride (2) were found to be the best BChE inhibitors and their affinities for the enzyme active site were about five times higher compared to the enzyme peripheral site. The strongest interaction observed in complexes obtained by docking studies was the H-bond between the guanidine and the carboxylate of Glu199 and the second guanidine group in bisguanidine compounds was stabilized with additional H-bonds.
一系列新型金刚烷取代的胍腙被合成出来，并用于研究其对丁酰胆碱酯酶的抑制潜力。实验结果进一步得到了 docking 研究的支持，该研究检查了抑制剂在酶活性部位的行为。用 Ellman 法测定胆碱酯酶活性，从 Hunter-Downs 图中确定酶-抑制剂解离常数 K(i)。发现 2-(N-胍基)亚氨基金刚烷盐酸盐（1）和 2,4-双（N,N'-胍基）亚氨基金刚烷二盐酸盐（2）是最好的 BChE 抑制剂，它们与酶活性部位的亲和力比酶外周部位高约五倍。通过对接研究获得的复合物中观察到的最强相互作用是胍基与 Glu199 的羧酸盐之间的氢键，并且双胍化合物中的第二个胍基与额外的氢键稳定。
