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Why medicines work
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2022-03-26 , DOI: 10.1016/j.pharmthera.2022.108175
David C Swinney 1
Affiliation  

The interactions of candidate medicines with physiology that have yielded therapeutics are a small subset of the total interactions investigated. To be useful the interactions must initiate molecular actions that fix a disease phenotype. While much is known about the targets for successful interactions and the disease phenotypes, much less is understood of the molecular actions that connect the initial interactions to specific phenotypic changes. Towards a better understanding of these actions, the first in class drugs (233) approved between 1999 and 2020 by the United States FDA were analyzed. The analysis identifies the actions that have been successful and characteristics of those actions. The medicines clustered into a relatively few specific actions: those that act on systems through sensors/receptors and controllers (51%), those that act to disrupt essential functions (12%), and those that act to provide a molecular fix by repair, removal, or silencing (33%). Antimicrobials were clustered with those that disrupt essential functions and antivirals were clustered in the molecular category. The sensor and controller actions work through system specific regulatory nodes whereby a single modality triggers a change to a complex system. Actions that disrupt functions cause toxicity and death to cells and organisms, where in many cases, mechanisms of repair and compensation play a role in both death and specificity. The molecular actions directly address known disease causes and arise from the intersection between enabling technologies that identify disease cause, and development of new modalities and their corresponding actions that provide therapeutic solutions. Many of the medicines utilize physiologic processes involving committed transitions at the core of the actions to enhance specificity. These actions, which process the input to specific output, are important for understanding why medicines work.



中文翻译:

为什么药物有效

候选药物与产生治疗的生理学的相互作用是所研究的总相互作用的一小部分。为了有用,相互作用必须启动修复疾病表型的分子作用。虽然对成功相互作用的目标和疾病表型了解很多,但对将初始相互作用与特定表型变化联系起来的分子作用知之甚少。为了更好地了解这些行动,对美国 FDA 于 1999 年至 2020 年间批准的同类首创药物 (233) 进行了分析。该分析确定了已成功的行动和这些行动的特征。这些药物集中在相对较少的具体行动中:通过传感器/受体和控制器作用于系统的药物(51%),那些破坏基本功能的物质(12%),以及通过修复、去除或沉默来提供分子修复的物质(33%)。抗微生物药物与破坏基本功能的药物聚集在一起,而抗病毒药物则聚集在分子类别中。传感器和控制器动作通过系统特定的监管节点工作,从而单一模式触发复杂系统的变化。破坏功能的行为会对细胞和生物体造成毒性和死亡,在许多情况下,修复和补偿机制在死亡和特异性中都起作用。分子作用直接解决已知的疾病原因,并产生于识别疾病原因的使能技术与新模式的开发及其提供治疗解决方案的相应行动之间的交叉点。许多药物利用生理过程,包括以行动为核心的承诺转换,以增强特异性。这些将输入处理为特定输出的操作对于理解药物为何起作用非常重要。

更新日期:2022-03-26
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