Macrocycles in Drug Discovery?Learning from the Past for the Future

被引:139
作者
Jimenez, Diego Garcia [1 ,2 ]
Poongavanam, Vasanthanathan [1 ]
Kihlberg, Jan [1 ]
机构
[1] Uppsala Univ, Dept Chem BMC, SE-75123 Uppsala, Sweden
[2] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10135 Turin, Italy
基金
瑞典研究理事会;
关键词
VIRUS NS3 PROTEASE; NATURAL-PRODUCT; PERMEABILITY; SOLUBILITY; MODALITIES; INHIBITOR; DESIGN; LEARN; SPACE; BIND;
D O I
10.1021/acs.jmedchem.3c00134
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80-90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30-40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD <= 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles.
引用
收藏
页码:5377 / 5396
页数:20
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