Molecular docking of glycogen synthase kinase3-β inhibitor oleanolic acid and its wound-healing activity in rats
Molecular docking of glycogen synthase kinase3-β inhibitor oleanolic acid and its wound-healing activity in rats
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DOI：
10.1007/s00044-012-0014-1
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发表时间：
2013-01-01
影响因子：
2.6
通讯作者：
Krishna, Venkatarangaiah
中科院分区：
文献类型：
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作者：
Ahamed, Khadeer B. M.;Gowdru, Harish Basavanthappa;Krishna, Venkatarangaiah
糖原合成酶激酶3- β (gsk3 - β)参与能量代谢、细胞发育和机体模式形成，其抑制作用通过β -卡丹素依赖的Wnt信号通路促进伤口愈合。通过Wnt信号通路研究了从太子参树皮甲醇提取物中分离的齐墩果酸与gsk3 - β的分子对接。与齐墩果酸对接的gsk3 - β激活域的抑制常数为1.55 × 10(-9)，而标准药物磺胺噻唑的抑制常数为9.27 × 10（-6）。采用大鼠切除、切口和死腔损伤模型研究了提取物和分离成分的效力。齐墩果酸（1% w/w软膏）处理的动物在伤后第16天上皮化速度更快，创面收缩率为96.82%。腹腔注射齐墩果酸（12 mg kg（-1）体重）后，切口创面抗拉强度显著提高至5800.832.95 g。在死腔伤口中，观察到重量、抗拉强度、羟脯氨酸含量和肉芽肿组织胶原增加显著增加。进一步的研究结果假设齐墩果酸可能通过β -catanin依赖性Wnt信号通路抑制gsk3 - β来发挥愈合活性。
Glycogen Synthase Kinase3-beta (GSK3-beta) is involved in energy metabolism, cell development, and body pattern formation, whose inhibition promotes wound healing through beta-catanin-dependent Wnt signaling pathway. Molecular Docking of oleanolic acid isolated from Methanolic extract of Grewia tiliaefolia bark to GSK3-beta was studied by Wnt signaling pathway. The activation domain of GSK3-beta docked with oleanolic acid showed the inhibition constant 1.55 x 10(-9) whereas, standard drug sulphathiazole showed inhibition constant of 9.27 x 10(-6). Both extract and isolated constituent were studied for their potency using excision, incision, and dead space wound models in rats. In oleanolic acid-treated animals (1 % w/w ointment cream base), epithelialization was faster with 96.82 % wound contraction on 16th post wounding day. Tensile strength of incision wound was significantly increased to 580.832.95 g after intraperitoneal administration of oleanolic acid (12 mg kg(-1) body weight). In dead space wound, a significant increase in weight, tensile strength, hydroxyproline content and increased collagenation of granuloma tissue was observed. Further in silico findings hypothesized that oleanolic acid may exert the healing activity by inhibiting GSK3-beta through beta-catanin-dependent Wnt signaling pathway.