复旦大学：《药物设计学》课程教学资源（电子课件）第一章 基于筛选途径的药物发现 Screening Based Drug Discovery

本科生《药物设计学》专业课 筛选途径的药物发现 Screening Based Drug Discovery 复旦大学药学院药物化学教研室 李炜 wei-li@fudan.edu.cn

筛选途径的药物发现 Screening Based Drug Discovery 复旦大学药学院药物化学教研室 李 炜 wei-li@fudan.edu.cn 本科生《药物设计学》专业课

Janssen PHARMACEUTICAL COMPANIES Paul Janssen(1926-2003)

Paul Janssen (1926-2003)

New medicines discovered by Janssen’ s tean OH N N H2c N haloperidol fentanyl NCH 3 N(CH3)2 N HO F CI risperidone loperamide More than 80 new medicines(absolute world record), at the wide range of his inventions in psychopharmacology, neuropharmacology, gastroenterology, cardiology, parasitology, virology, immunology, anaesthesiology, and analgesia

New medicines discovered by Janssen’s team haloperidol risperidone fentanyl loperamide More than 80 new medicines (absolute world record), at the wide range of his inventions in psychopharmacology, neuropharmacology, gastroenterology, cardiology, parasitology, virology, immunology, anaesthesiology, and analgesia

Classic of Phenotypic screening Iterative evolution process Conception A lead compd Test feedback A picture of Appropriate Synthesis Bioassay structure- bioassay Unmet evaluation activit relationship medical need Active in least 3 /5 authentic exovivo or in vivo pharmacological models When Fit for its purpose? Judgment Experience Workup Creativity Imagination Aesthetic intuition -A concept-driven project

Classic of Phenotypic screening Conception A lead compd Appropriate bioassay Unmet medical need Iterative evolution process Synthesis Bioassay evaluation Test feedback A picture of structure￾activity relationship Active in least 3/5 authentic exo-vivo or in vivo pharmacological models When Fit for its purpose? Judgment Experience Imagination Aesthetic intuition —— A concept-driven project Workup Creativity When Fit for its purpose? Judgment Experience Imagination Aesthetic intuition

Real-world Screening based Drug discovery 天然 成 药物化学家 微生 药理学家 物 先导化合物 Main concerns DIVERSITY THROUGHPUT TRANSLATION

Real-world Screening based Drug discovery 药物化学家 药理学家 先导化合物 微生 物 天然 产物 合成 Main concerns DIVERSITY THROUGHPUT TRANSLATION

What did a medicinal chemist say ? Harvard Medical school/Mclean Hospital Matthews Distinguished Professor 创办 Research Biochemicals nternational(RB)公司 °已发表280多篇学术论文,获20项美 国专利 Prof, dr John l Neumeyer ●发明帕金森氏症诊断药 DATSCAN Reference: Chem. Rev., 2013, 113(5), pp PR123-PR178

Prof. Dr. John L. Neumeyer • Harvard Medical School/McLean Hospital • Matthews Distinguished Professor • 创办Research Biochemicals International （RBI）公司 • 已发表280多篇学术论文，获20项美 国专利 • 发明帕金森氏症诊断药DATSCAN® Reference: Chem. Rev., 2013, 113 (5), pp PR123–PR178 What did a medicinal chemist say?

Most important lessons from my career (D) Sound background skills in Organic Chemistry 良好的有机化学背景及实验技能 Good understanding knowledge of related biochemistry and pharmacology 对所关注的生化及药理机制有深刻的理解 和认识

Most important lessons from my career （I） • Sound background & skills in Organic Chemistry 良好的有机化学背景及实验技能 • Good understanding & knowledge of related biochemistry and pharmacology 对所关注的生化及药理机制有深刻的理解 和认识

Most important lessons from my career(Ⅲ) Find good collaborator(s)in pharmacology and clinical sciences 在药理学及临床科学领域维持良好的合作 伙伴关系 Patience 持之以恒

Most important lessons from my career （II） • Find good collaborator(s) in pharmacology and clinical sciences 在药理学及临床科学领域维持良好的合作 伙伴关系 • Patience 持之以恒

筛选途径需要解决的基本问题 结构多样性( Diversity) 转化医学( Translation| Medicine, from bench to bedside)

筛选途径需要解决的基本问题 I. 结构多样性（Diversity） II. 转化医学（Translational Medicine, from bench to bedside）

药物设计基本原理 多样性 Diversity 药物分子的多样性 天然产物提取分离、 合成以及半合成 合成化合物的筛选 组合化学 View of Pub chem chemical space Reymond, JL, ACS Chem. Neurosci. 39) 649-657

药物设计基本原理—— 多样性 Diversity • 药物分子的多样性 • 天然产物提取分离、 合成以及半合成 • 合成化合物的筛选 • 组合化学 View of PubChem chemical space Reymond, J.L, ACS Chem. Neurosci. 3 (9): 649–657