Abolhasani Hoda, Zarghi Afshin, Hamzeh-Mivehroud Maryam, Alizadeh Ali Akbar, Shahbazi Mojarrad Javid, Dastmalchi Siavoush
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2015 Winter;14(1):141-7.
Interference with microtubule polymerization results in cell cycle arrest leading to cell death. Colchicine is a well-known microtubule polymerization inhibitor which does so by binding to a specific site on tubulin. A set of 3', 4'-bis (substituted phenyl)-4'H-spiro [indene-2, 5'-isoxazol]-1(3H)-one derivatives with known antiproliferative activities were evaluated for their tubulin binding modes. 3D structures of the derivatives were docked into the colchicine binding site of tubulin using GOLD 5.0 program under flexible ligand and semi-flexible receptor condition. The spiroisoxazoline derivatives bind tubulin in a similar manner to colchicine by establishing at least a hydrogen bonding to Cys(241) as well as hydrophobic interactions with Leu(255), Ile(378) and Lys(254) and few other residues at the binding pocket. It can be concluded that the spiroisoxazoline core structure common to the studied derivatives is a suitable scaffold for placing the antitubulin pharmacophoric groups in appropriate spatial positions required for tubulin binding activity.
干扰微管聚合会导致细胞周期停滞，进而导致细胞死亡。秋水仙碱是一种著名的微管聚合抑制剂，它通过与微管蛋白上的特定位点结合来实现这一作用。对一组具有已知抗增殖活性的3'，4'-双（取代苯基）-4'H-螺[茚-2,5'-异恶唑]-1(3H)-酮衍生物的微管蛋白结合模式进行了评估。在柔性配体和半柔性受体条件下，使用GOLD 5.0程序将衍生物的三维结构对接至微管蛋白的秋水仙碱结合位点。螺异恶唑啉衍生物通过与半胱氨酸（241）至少建立一个氢键以及与亮氨酸（255）、异亮氨酸（378）、赖氨酸（254）和结合口袋中的其他几个残基进行疏水相互作用，以与秋水仙碱相似的方式结合微管蛋白。可以得出结论，所研究衍生物共有的螺异恶唑啉核心结构是一个合适的支架，可将抗微管蛋白药效基团置于微管蛋白结合活性所需的适当空间位置。
