药学学报 Acta pharmaceutica sinica2016,51(3):325-331 325 ·专家论坛· 药物创新与反向思维 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:创制新药是个性化的分子操作,各自都有难以复制的研发轨迹。将活性化合物转化成药物的过程,几 乎是在没有规律性、没有周期性变化的混沌系统中进行的。自21世纪以来上市的新分子实体以首创性药物占主 导地位,跟进式药物明显减少。研制首创性药物风险大,并贯穿于始终。为了突出首创性乃至唯一性的新药,反 向思维的策略和方法或许是一条可行的路径。惯性和从众性的正向思维往往导致同类新药的聚集,从事物(如靶 标或效应)的反面或对立面考察、探索和研究,有可能另辟蹊径。本文试图用阿片受体拮抗剂依卢多林、HSP90 激动剂、hERG通道激动剂、大环内酯类胃动素激动剂、共价键药物和超小分子药物等一些实例阐述反向思维的 策略运用。 关键词:反向思维,阿片受体拮抗剂;HSP90激动剂;hERG通道激动剂;共价键药物 中图分类号:R916 文献标识码:A 文章编号:0513-4870(2016)03-0325-07 Drug innovation and reverse thinking GUO Zong-ru (listitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China Abstract: Drug innovation involves an individual molecular operation, and every new molecular entity atures a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things(e. g. targets or effects)brand new routes might be opened. This article is to describe the strategy reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, hERG channel agonist, covalent drugs, and ultra-small drugs Key words: reverse thinking; opioid receptor antagonist; HSP90 activator, hERG channel agonist; covalent “十三五重大新药创制”倡导和鼓励研制首创明显减少,彰显了首创药物的主导地位。以靶标为 性药物,标志着国家发展到新的水平,也体现了当今核心的药物创新模式,是以分子和细胞生物学基础 临床与市场对新药的需求。本世纪以来的跟进式新药研究为引擎,发现新的生物功能分子,过渡到以化学 生物学为主导的探针与靶标分子的互动,再引申到 与药物化学对接,进入新药研发的轨道。在这探针 收稿日期:2015-12-07,修回日期:2016-01-07 ◆通讯作者Te:86-10-83155752,E-mail: zreuo aimm.ac 先导物-候选物一新药批准的全过程中,靶标的确证 DOl:10.16438/05134870.2015-1117 贯穿于始终。这是一条“定型”的主流研发模式,本药学学报 Acta Pharmaceutica Sinica 2016, 51 (3): 325 −331 · 325 · 药物创新与反向思维 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: 创制新药是个性化的分子操作, 各自都有难以复制的研发轨迹。将活性化合物转化成药物的过程, 几 乎是在没有规律性、没有周期性变化的混沌系统中进行的。自 21 世纪以来上市的新分子实体以首创性药物占主 导地位, 跟进式药物明显减少。研制首创性药物风险大, 并贯穿于始终。为了突出首创性乃至唯一性的新药, 反 向思维的策略和方法或许是一条可行的路径。惯性和从众性的正向思维往往导致同类新药的聚集, 从事物 (如靶 标或效应) 的反面或对立面考察、探索和研究, 有可能另辟蹊径。本文试图用阿片受体拮抗剂依卢多林、HSP90 激动剂、hERG 通道激动剂、大环内酯类胃动素激动剂、共价键药物和超小分子药物等一些实例阐述反向思维的 策略运用。 关键词: 反向思维; 阿片受体拮抗剂; HSP90 激动剂; hERG 通道激动剂; 共价键药物 中图分类号: R916 文献标识码: A 文章编号: 0513-4870 (2016) 03-0325-07 Drug innovation and reverse thinking GUO Zong-ru* (Iistitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China ) Abstract: Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things (e.g. targets or effects) brand new routes might be opened. This article is to describe the strategy of reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, hERG channel agonist, covalent drugs, and ultra-small drugs. Key words: reverse thinking; opioid receptor antagonist; HSP90 activator; hERG channel agonist; covalent drug “十三五重大新药创制”倡导和鼓励研制首创 性药物, 标志着国家发展到新的水平, 也体现了当今 临床与市场对新药的需求。本世纪以来的跟进式新药 收稿日期: 2015-12-07; 修回日期: 2016-01-07. *通讯作者 Tel: 86-10-83155752, E-mail: zrguo@imm.ac.cn DOI: 10.16438/j.0513-4870.2015-1117 明显减少, 彰显了首创药物的主导地位[1]。以靶标为 核心的药物创新模式, 是以分子和细胞生物学基础 研究为引擎, 发现新的生物功能分子, 过渡到以化学 生物学为主导的探针与靶标分子的互动, 再引申到 与药物化学对接, 进入新药研发的轨道。在这探针− 先导物−候选物−新药批准的全过程中, 靶标的确证 贯穿于始终。这是一条“定型”的主流研发模式, 本 ·专家论坛·