Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis
Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis
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DOI：
10.1021/jm0102811
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发表时间：
2002-07-18
影响因子：
7.3
通讯作者：
Welsh, WJ
中科院分区：
文献类型：
--
作者：
Farr, CD;Tabet, MR;Welsh, WJ
本研究表明，新产生的人序列抗地高辛单抗1B3与地高辛结合具有不同于我们以前获得的人序列单抗(MAbs)的精细特异性结合(Ball，W.J.；等人)。J.免疫。1999、163、2291-2298)。独一无二的是，1B3对洋地黄毒素的亲和力高于地高辛，地高辛是免疫半抗原，并且对至少一个与苷元(-Genin)相连的糖基残基有强烈的要求。通过比较分子场分析(CoMFA)，利用56个强心和激素类化合物的竞争结合研究结果，建立了配体与1B3和另外3个人序列单抗以及小鼠抗地高辛单抗40-50(Mudgett-Hunter，M.；等)结合的三维定量构效关系(3D-QSAR)模型。摩尔。免疫系统。1985、22,447-488)。所有5个3D-QSAR模型的交叉验证Q(2)值均大于0.5，表明它们具有显著的预测能力。CoMFA stdev*Coff等值线图以及竞争结果表明，1B3以一种不同于其他四种单抗的方式与配体结合。40-50的CoMFA等高线图也与已知的40-50-哇巴因络合物的X射线晶体结构进行了比较(Jeffrey，P.D.；等人。J.Mol.比奥尔。1995、248、344-360)，以确定单抗结合部位的残基与特定等高线图区之间的相关性。这些3D-QSAR模型和它们各自的等高线图应该是有用的工具，以进一步了解抗体-抗原相互作用的分子性质，并帮助重新设计或增强治疗性抗体。
The present study indicates that the newly generated human sequence antidigoxin monoclonal antibody (mAb), 1B3, binds digoxin with a different fine specificity binding than our previously obtained human sequence monoclonal antibodies (mAbs) (Ball, W. J.; et al. J. Immunol. 1999, 163, 2291-2298). Uniquely, 1B3 has a higher affinity for digitoxin than digoxin, the immunizing hapten, and a strong requirement for at least one sugar residue linked to the aglycone (-genin). By means of comparative molecular field analysis (CoMFA), the results of competition binding studies for 56 cardiotonic and hormonal steroids were employed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models for ligand binding to 1B3 and to three additional human sequence mAbs, as well as the murine antidigoxin mAb 40-50 (Mudgett-Hunter, M.; et al. Mol. Immunol. 1985,22,447-488). All five 3D-QSAR models yielded cross-validated q(2) values greater than 0.5, which indicates that they have significant predictive ability. The CoMFA StDev*Coeff contour plots, as well as the competition results, indicate that 1B3 binds ligands in a manner distinct from the other four mAbs. The CoMFA contour plots for 40-50 were also compared with the known X-ray crystallographic structure of the 40-50-ouabain complex (Jeffrey, P. D.; et al. J. Mol. Biol. 1995, 248, 344-360) in order to identify correlations between residues in the mAb binding site and specific contour plot regions. These 3D-QSAR models and their respective contour plots should be useful tools to further understand the molecular nature of antibody-antigen interactions and to aid in the redesign or enhancement of therapeutic antibodies..