Matsson Pär, Kihlberg Jan
Department of Pharmacy, BMC, Uppsala University , Box 580, SE-751 23 Uppsala, Sweden.
Department of Chemistry, BMC, Uppsala University , Box 576, SE-751 23 Uppsala, Sweden.
J Med Chem. 2017 Mar 9;60(5):1662-1664. doi: 10.1021/acs.jmedchem.7b00237. Epub 2017 Feb 24.
Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein-protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.
了解如何设计针对具有难以结合位点的细胞内靶点（如蛋白质-蛋白质相互作用）的细胞渗透性配体，将为药物发现带来巨大机遇。有趣的是，环状肽库在分子量高于1000 Da时膜渗透性急剧下降，而且对于更具药物样特性的化合物来说，这个界限似乎也构成了一个大小上限。然而，500至1000 Da的化学空间几乎尚未被探索，对于那些准备涉足药物发现新领域的人来说，这是一个巨大的机会。
