Zhou Peng, Tian Feifei, Shang Zhicai
Institute of Molecular Design & Molecular Thermodynamics, Department of Chemistry, Zhejiang University, Hangzhou, China.
Chem Biol Drug Des. 2008 Dec;72(6):525-32. doi: 10.1111/j.1747-0285.2008.00733.x.
With the number of solved protein/ligand complex 3D structures growing up rapidly in recent years, lead modification and optimization based on the complex structure have received much attention in drug design community. In this study, we propose a novel method LigEvolutioner for the purpose of lead optimization in protein/ligand complexes. Using a fragment substitution strategy in the context of evolutionary algorithm, LigEvolutioner can analyze the complex structures automatically and derive several modification projects that could possibly improve the binding affinity of ligands. For instance, LigEvolutioner was employed to analyze and modify antigenic peptide ligand in human HLA-A*0201/peptide complexes and, as a result, a peptide analogue with potential high affinity was designed. The structure configuration of this modified peptide is consistent with crystal profile and antigen presenting theory. In addition, we have confirmed the validity of LigEvolutioner by systematically comparing it with several widely used scoring methods.
近年来，随着已解析的蛋白质/配体复合物三维结构数量迅速增长，基于复合物结构的先导化合物修饰和优化在药物设计领域受到了广泛关注。在本研究中，我们提出了一种名为LigEvolutioner的新方法，用于蛋白质/配体复合物的先导化合物优化。LigEvolutioner在进化算法的框架下采用片段替换策略，能够自动分析复合物结构并推导多个可能提高配体结合亲和力的修饰方案。例如，LigEvolutioner被用于分析和修饰人HLA-A*0201/肽复合物中的抗原肽配体，结果设计出了一种具有潜在高亲和力的肽类似物。这种修饰后肽的结构构型与晶体图谱和抗原呈递理论一致。此外，通过与几种广泛使用的评分方法进行系统比较，我们证实了LigEvolutioner的有效性。
