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首页> 外文期刊>Journal of Molecular Biology >Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis.
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Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis.

机译：可卡因与两种单克隆抗体结合的三维结构-活性关系模型通过比较分子场分析。

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Successful immunotherapy of cocaine addiction and overdoses requires cocaine-binding antibodies with specific properties, such as high affinity and selectivity for cocaine. We have determined the affinities of two cocaine-binding murine monoclonal antibodies (mAb: clones 3P1A6 and MM0240PA) for cocaine and its metabolites by [3H]-radioligand binding assays. mAb 3P1A6 (K(d) = 0.22 nM) displayed a 50-fold higher affinity for cocaine than mAb MM0240PA (K(d) = 11 nM) and also had a greater specificity for cocaine. For the systematic exploration of both antibodies' binding specificities, we used a set of approximately 35 cocaine analogues as structural probes by determining their relative binding affinities (RBAs) using an enzyme-linked immunosorbent competition assay. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models on the basis of comparative molecular field analysis (CoMFA) techniques correlated the binding data with structural features of the ligands. The analysis indicated that despite the mAbs' differing specificities for cocaine, the relative contributions of the steric (approximately 80%) and electrostatic (approximately 20%) field interactions to ligand-binding were similar. Generated three-dimensional CoMFA contour plots then located the specific regions about cocaine where the ligand/receptor interactions occurred. While the overall binding patterns of the two mAbs had many features in common, distinct differences were observed about the phenyl ring and the methylester group of cocaine. Furthermore, using previously published data, a 3D-QSAR model was developed for cocaine binding to the dopamine reuptake transporter (DAT) that was compared to the mAb models. Although the relative steric and electrostatic field contributions were similar to those of the mAbs, the DAT cocaine-binding site showed a preference for negatively charged ligands. Besides establishing molecular level insight into the interactions that govern cocaine binding specificity by biopolymers, the three-dimensional images obtained reflect the properties of the mAbs binding pockets and provide the initial information needed for the possible design of novel antibodies with properties optimized for immunotherapy.
机译：成功的可卡因成瘾和过量用药免疫疗法需要具有特定特性（例如对可卡因的高亲和力和选择性）的可卡因结合抗体。我们已经通过[3H]-放射配体结合测定法确定了两种可卡因结合鼠单克隆抗体（mAb：3P1A6和MM0240PA克隆）对可卡因及其代谢物的亲和力。与mAb MM0240PA（K（d）= 11 nM）相比，mAb 3P1A6（K（d）= 0.22 nM）显示出对可卡因的亲和力高50倍，并且对可卡因的特异性也更高。为了系统地研究两种抗体的结合特异性，我们通过使用酶联免疫吸附竞争测定法确定它们的相对结合亲和力（RBA），使用了大约35种可卡因类似物作为结构探针。基于比较分子场分析（CoMFA）技术的三维定量构效关系（3D-QSAR）模型将结合数据与配体的结构特征相关联。分析表明，尽管单克隆抗体对可卡因的特异性不同，但空间（约80％）和静电（约20％）场相互作用对配体结合的相对贡献是相似的。然后，生成的三维CoMFA等高线图位于可卡因周围发生配体/受体相互作用的特定区域。尽管两种mAb的整体结合模式具有许多共同的特征，但可卡因的苯环和甲酯基却观察到了明显的差异。此外，使用以前发表的数据，开发了一种3D-QSAR模型，用于将可卡因与多巴胺再摄取转运蛋白（DAT）结合，并将其与mAb模型进行比较。尽管相对空间和静电场贡献与mAb相似，但DAT可卡因结合位点显示出对带负电荷配体的偏爱。除了在分子水平上了解通过生物聚合物控制可卡因结合特异性的相互作用外，获得的三维图像还反映了mAbs结合口袋的特性，并提供了可能设计具有针对免疫疗法优化的特性的新型抗体所需的初始信息。

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