Three-dimensional quantitative structure-activity relationship modeling of cocaine binding by a novel human monoclonal antibody
Three-dimensional quantitative structure-activity relationship modeling of cocaine binding by a novel human monoclonal antibody
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DOI：
10.1021/jm030351z
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发表时间：
2004-01-01
影响因子：
7.3
通讯作者：
Ball, WJ
中科院分区：
文献类型：
--
作者：
Paula, S;Tabet, MR;Ball, WJ
设计用于免疫治疗的人单克隆抗体（mAb）具有很高的潜力，以避免可能由人免疫系统对将非人mAb引入患者中的反应引起的并发症。本研究采用三维定量构效关系（3D-QSAR）方法表征可卡因/抗体相互作用，确定新型人序列mAb 2 E2的结合特性。我们已经通过实验确定了mAb 2 E2对可卡因和38种可卡因类似物的结合亲和力。mAb 2 E2对可卡因的Kd为4 nM，表明具有高亲和力。此外，单克隆抗体2 E2显示良好的可卡因特异性，反映在其10-，1500-，和25000倍的结合亲和力较低的三个生理相关的可卡因代谢物苯甲酰芽子碱，芽子碱甲酯，和芽子碱，分别。采用比较分子相似性指数分析法（CoMSIA）建立了可卡因结合的3D-QSAR模型。生成了高统计质量的模型，显示可卡因在空间受限的结合位点与mAb 2 E2结合，该结合位点使连接至可卡因环氮的甲基暴露于溶剂。可卡因的甲基酯基团似乎与mAb 2 E2进行有吸引力的货车范德华相互作用，而苯基基团主要通过疏水相互作用促进结合。该模型进一步表明，氮质子和甲酯羰基附近部分正电荷的增加增强了结合亲和力，酯氧可能与mAb 2 E2形成分子间氢键。总体而言，mAb 2 E2的可卡因结合特性支持其开发为可卡因过量和成瘾治疗的临床潜力。
Human monoclonal antibodies (mAbs) designed for immunotherapy have a high potential for avoiding the complications that may result from human immune system responses to the introduction of nonhuman mAbs into patients. This study presents a characterization of cocaine/antibody interactions that determine the binding properties of the novel human sequence mAb 2E2 using three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology. We have experimentally determined the binding affinities of mAb 2E2 for cocaine and 38 cocaine analogues. The K-d of mAb 2E2 for cocaine was 4 nM, indicating a high affinity. Also, mAb 2E2 displayed good cocaine specificity, as reflected in its 10-, 1500-, and 25000-fold lower binding affinities for the three physiologically relevant cocaine metabolites benzoylecgonine, ecgonine methyl ester, and ecgonine, respectively. 3D-QSAR models of cocaine binding were developed by comparative molecular similarity index analysis (CoMSIA). A model of high statistical quality was generated showing that cocaine binds to mAb 2E2 in a sterically restricted binding site that leaves the methyl group attached to the ring nitrogen of cocaine solvent-exposed. The methyl ester group of cocaine appears to engage in attractive van der Waals interactions with mAb 2E2, whereas the phenyl group contributes to the binding primarily via hydrophobic interactions. The model further indicated that an increase in partial positive charge near the nitrogen proton and methyl ester carbonyl group enhances binding affinity and that the ester oxygen likely forms an intermolecular hydrogen bond with mAb 2E2. Overall, the cocaine binding properties of mAb 2E2 support its clinical potential for development as a treatment of cocaine overdose and addiction.