Williams Glyn, Ferenczy György G, Ulander Johan, Keserű György M
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
Drug Discov Today. 2017 Apr;22(4):681-689. doi: 10.1016/j.drudis.2016.11.019. Epub 2016 Dec 1.
Small is beautiful - reducing the size and complexity of chemical starting points for drug design allows better sampling of chemical space, reveals the most energetically important interactions within protein-binding sites and can lead to improvements in the physicochemical properties of the final drug. The impact of fragment-based drug discovery (FBDD) on recent drug discovery projects and our improved knowledge of the structural and thermodynamic details of ligand binding has prompted us to explore the relationships between ligand-binding thermodynamics and FBDD. Information on binding thermodynamics can give insights into the contributions to protein-ligand interactions and could therefore be used to prioritise compounds with a high degree of specificity in forming key interactions.
小即美——减小药物设计化学起始点的尺寸和复杂性，能够更好地对化学空间进行取样，揭示蛋白质结合位点内能量上最为重要的相互作用，并可能改善最终药物的物理化学性质。基于片段的药物发现（FBDD）对近期药物发现项目的影响以及我们对配体结合的结构和热力学细节的深入了解，促使我们探索配体结合热力学与FBDD之间的关系。结合热力学信息可以深入了解对蛋白质-配体相互作用的贡献，因此可用于对在形成关键相互作用方面具有高度特异性的化合物进行优先级排序。
