Maurer Tristan S, Edwards Martin, Hepworth David, Verhoest Patrick, Allerton Charlotte M N
Department of Medicine Design, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
Department of Medicine Design, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA.
Drug Discov Today. 2022 Feb;27(2):538-546. doi: 10.1016/j.drudis.2021.09.017. Epub 2021 Sep 30.
Successful small-molecule drug design requires a molecular target with inherent therapeutic potential and a molecule with the right properties to unlock its potential. Present-day drug design strategies have evolved to leave little room for improvement in drug-like properties. As a result, inadequate safety or efficacy associated with molecular targets now constitutes the primary cause of attrition in preclinical development through Phase II. This finding has led to a deeper focus on target selection. In this current reality, design tactics that enable rapid identification of risk-balanced clinical candidates, translation of clinical experience into meaningful differentiation strategies, and expansion of the druggable proteome represent significant levers by which drug designers can accelerate the discovery of the next generation of medicines.
成功的小分子药物设计需要一个具有内在治疗潜力的分子靶点，以及一个具有合适特性以释放其潜力的分子。如今的药物设计策略已经发展到在类药性质方面几乎没有改进空间。因此，与分子靶点相关的安全性或有效性不足现在已成为从临床前开发到二期临床阶段药物研发失败的主要原因。这一发现促使人们更加关注靶点选择。在当前这种现实情况下，能够快速识别风险平衡的临床候选药物、将临床经验转化为有意义的差异化策略以及扩大可成药蛋白质组的设计策略，是药物设计师加速发现下一代药物的重要手段。
