Computer-aided antibody design.
Computer-aided antibody design.
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DOI：
10.1093/protein/gzs024
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Nakamura H
中科院分区：
文献类型：
--
作者：
Kuroda D;Shirai H;Jacobson MP;Nakamura H
最近使用低毒性和高效率抗体的临床试验提高了对下一代蛋白质治疗剂开发的期望。然而，获得治疗性抗体的过程仍然是耗时和经验性的。本文综述了计算机辅助抗体开发领域的最新进展，主要集中在抗体建模方面，主要分为两个部分：（i）抗原结合位点的建模，也称为互补决定区（CDR）;（ii）预测可变重链（VH）和轻链（VL）的相对取向。在六个CDR环中，最大的挑战是预测在抗原识别中最重要的CDR-H3的构象。进一步的计算方法可以用于基于晶体结构或同源模型的药物开发，包括抗体-抗原对接和近似势函数的能量计算。这些方法应指导实验研究，以提高抗体的亲和力和理化性质。最后，几个成功的例子，在硅结构为基础的抗体设计进行了审查。我们还简要回顾了基于结构的抗原或免疫原设计，与合理的疫苗开发的应用。
Recent clinical trials using antibodies with low toxicity and high efficiency have raised expectations for the development of next-generation protein therapeutics. However, the process of obtaining therapeutic antibodies remains time consuming and empirical. This review summarizes recent progresses in the field of computer-aided antibody development mainly focusing on antibody modeling, which is divided essentially into two parts: (i) modeling the antigen-binding site, also called the complementarity determining regions (CDRs), and (ii) predicting the relative orientations of the variable heavy (VH) and light (VL) chains. Among the six CDR loops, the greatest challenge is predicting the conformation of CDR-H3, which is the most important in antigen recognition. Further computational methods could be used in drug development based on crystal structures or homology models, including antibody–antigen dockings and energy calculations with approximate potential functions. These methods should guide experimental studies to improve the affinities and physicochemical properties of antibodies. Finally, several successful examples of in silico structure-based antibody designs are reviewed. We also briefly review structure-based antigen or immunogen design, with application to rational vaccine development.
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