药学学报, 2013, 48(12): 1755-1762
引用本文:
郭宗儒. 化合物效率与先导物优化[J]. 药学学报, 2013, 48(12): 1755-1762.
GUO Zong-ru. Ligand efficiency and lead optimization[J]. Acta Pharmaceutica Sinica, 2013, 48(12): 1755-1762.

化合物效率与先导物优化
郭宗儒
中国医学科学院、北京协和医学院药物研究所, 北京 100050
摘要:
活性和成药性是药物的两大支柱,分别是由分子的微观结构与宏观性质所决定。结构的优化是在多维度空间中进行的多参数分子操作。由体外活性过渡到体内的药理效应有许多不确定性,需要在早期优化阶段用分子的多维度规(metrics)评价化合物的质量或效率。本文在讨论表征化合物活性和成药性参数的基础上,阐述调整微观结构中药物-受体结合热力学的焓与熵、结合动力学的离解速率对提高化合物效率的影响,说明优化微观结构对成药性的重要意义。
关键词:    化合物效率      成药性      微观结构      慢离解药物     
Ligand efficiency and lead optimization
GUO Zong-ru
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Pharmacological activity and druggability are two pivotal factors in drug innovation, which are respectively determined by the microscopic structure and macroscopic property of a molecule. Since structural optimization consists in a molecular operation in the space with multi-dimensions, and there exists a body of uncertainties for transduction from in vitro activity into in vivo pharmacological response. It is necessary for early stage in lead optimization to evaluate compound quality or efficiency using a kind of metrics containing multi-parameters. On the basis of the describing parameters of activity and druggability, this overview deals with the roles of thermodynamic signatures and binding kinetics of drug-receptor interactions in optimizing quality of compounds, signifying the significance in optimization of microscopic structures for drug discovery.
Key words:    ligand efficiency    druggability    microscopoic structure    slow-offset drug   
收稿日期: 2013-07-18
通讯作者: 郭宗儒
Email: zrguo@imm.ac.cn
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