基于靶标结构理性设计的替拉那韦

发布时间：2018-08-12 14:53

【摘要】：新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。药物与靶标分子的相互作用是药效的原动力,基于靶标的三维结构"量体裁衣"式的设计新药,应是最理性的方法。靶标分子的柔性构象与不同化合物结合的多样性是基于结构的药物设计(SBDD)的难点之一。分子量较小的HIV蛋白酶是对称的二聚体,容易获得复合物单晶,所以在由香豆素演化成最终的替拉那韦的历程中,在多个节点处解析了复合物结构,辅助了设计。即使这样,还有许多需要探索的未知内容,因而,应用药物化学的原理和策略,不断驱动着SBDD的进程。替拉那韦的研制特点在于由苗头过渡到先导物乃至先导物优化,SBDD+药物化学方法贯穿于全过程。
[Abstract]:New drug creation is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own R & D track, and the construction of chemical structures is the most important step because it covers pharmacodynamics, pharmacology, safety and biopharmaceutical properties. This column analyzes and interprets the successful construction of representative drugs from the perspective of drug chemistry. The interaction between drugs and target molecules is the driving force of drug efficacy. The design of new drugs based on the three-dimensional structure of target should be the most rational method. The diversity of the flexible conformation of target molecules combined with different compounds is one of the difficulties in structure-based drug design (SBDD). The HIV protease with small molecular weight is a symmetric dimer, which makes it easy to obtain complex single crystals. Therefore, in the course of the evolution from coumarin to telanavir, the complex structure was analyzed at several nodes and the design was aided. Even so, there are still many unknown things to explore, so the application of the principles and strategies of pharmacochemistry drives the process of SBDD. The preparation of telanavir is characterized by the transition from seedling to pilot and even optimization of SBDD pharmacochemical method throughout the whole process.
【作者单位】：中国医学科学院北京协和医学院药物研究所;
【分类号】：R91

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