药物创新与反向思维

Drug innovation and reverse thinking

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、h ERG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。

Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of RD. 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, h ERG channel agonist, covalent drugs, and ultra-small drugs.