化合物效率及先导物优化.pdfVIP

药学学报 Acta Pharmaceutica Sinica 20 13, 48 ( 12): 1755 1762 ·1755 · 合物效率与先导物优 郭宗儒* ( 中国医学科学院、北京协和医学院 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 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 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 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 中图分类号: R9 16 文献标识码: A 文章编号: 0513-4870 (20 13) 12- 1755-08 Ligand efficiency and lead optimization * GUO Zong-ru (Ins titute of Materia Medica, Chinese Ac ademy of Medical Sciences and Peking Union Medical College, Beij ing 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