Liang Ting-Ting, Zhao Qi, He Shan, Mu Fang-Zhou, Deng Wei, Han Bing-Nan
School of Chemical and Environmental Engineering, Shanghai Institute of Technology.
Department of Development Technology of Marine Resources, College of Life Sciences, Zhejiang Sci-Tech University.
Chem Pharm Bull (Tokyo). 2018;66(6):602-607. doi: 10.1248/cpb.c17-00966.
Dolastatin 16 is a cyclic depsipeptide isolated from the marine invertebrates and cyanobacterium Lyngbya majuscula, however, its bioactivity has been a historical question. In this study, peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP12) was predicted as a potential target of dolastatin 16 via PharmMapper as well as verified using chemical-protein interactome (CPI) and molecular docking. FKBP1A has been previously identified as a target for the natural polyketide FK506 (tacrolimus), an immune suppressor inhibiting the rejection of organ transplantation in clinical use. The comparison study via the reverse pharmacophore screening and molecular docking of dolastatin 16 and FK506 indicated the good consistency of analysis with the computational approach. As the results, the lowest binding energy of dolastatin 16-FKBP1A complex was -7.4 kcal/mol and FK506-FKBP1A complex was -8.7 kcal/mol. The ligand dolastatin 16 formed three hydrogen bonds vs. four of FK506, as well as seven hydrophobic interactions vs. six of FK506 within the active site residues. These functional residues are highly repetitive and consistent with previously reported active site of model of FK506-FKBP1A complex, and the pharmacophore model was shown feasibly matching with the molecular feature of dolastatin 16.
多拉司他汀16是一种从海洋无脊椎动物和蓝藻巨大鞘丝藻中分离出的环缩肽，然而，其生物活性一直是个历史问题。在本研究中，肽基脯氨酰顺反异构酶FKBP1A（FKBP12）通过PharmMapper被预测为多拉司他汀16的潜在靶点，并使用化学-蛋白质相互作用组（CPI）和分子对接进行了验证。FKBP1A先前已被确定为天然聚酮化合物FK506（他克莫司）的靶点，FK506是一种免疫抑制剂，在临床中用于抑制器官移植排斥反应。通过对多拉司他汀16和FK506进行反向药效团筛选和分子对接的比较研究表明，该分析与计算方法具有良好的一致性。结果显示，多拉司他汀16 - FKBP1A复合物的最低结合能为-7.4千卡/摩尔，FK506 - FKBP1A复合物的最低结合能为-8.7千卡/摩尔。配体多拉司他汀16形成了3个氢键，而FK506形成了4个氢键，在活性位点残基内，多拉司他汀16形成了7个疏水相互作用，而FK506形成了6个疏水相互作用。这些功能残基具有高度重复性，与先前报道的FK506 - FKBP1A复合物模型的活性位点一致，并且药效团模型显示与多拉司他汀16的分子特征匹配良好。
