期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 35, 期 1, 页码 1800-1810出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2020.1816996
关键词
Carbonic anhydrase IX; carborane; enzyme inhibitors; structure-activity relationship
资金
- Czech Science Foundation [18-27648S]
- Technology Agency of the Czech Republic [TE01020028]
- European Regional Development Fund [CZ.02.1.01/0.0/0.0/16_019/0000729]
- PPLZ of the Czech Academy of Sciences [L200321851]
Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities bothin vitroandin vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.
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