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Structure-Based Design of FXIIIa-Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-04-07 , DOI: 10.1002/cmdc.202000056
Martin Stieler 1 , Christian Büchold 2 , Marisa Schmitt 2 , Andreas Heine 1 , Martin Hils 2 , Ralf Pasternack 2 , Gerhard Klebe 1
Affiliation  

Blood coagulation factor XIII (FXIII, F13) is considered to be a promising target for anticoagulants with reduced bleeding risk because of its unique position in the coagulation cascade downstream of thrombin. However, until now, no potent drug addressing FXIII has been available, indeed no compound has even entered clinical trials yet. In 2013, we published the co-crystal structure of FXIII in the active state (FXIIIa°), thereby providing a detailed map of the active site for the rational design of potent FXIIIa blockers. Here we report, for the first time, a structure-based approach to improving the affinity of FXIIIa inhibitors. FXIII was crystallized in complex with a methyl thiazole moiety to address a novel transient hydrophobic pocket close to the catalytic center. By subsequent structure-based design to rationalize the introduction of an ethyl ester, the potency of the inhibitor was improved significantly compared to that of the parent lead compound. The occupancy of the hydrophobic pocket described here might turn out to be a key step in the development of a potent reversible and orally available FXIIIa blocker.

中文翻译:

FXIIIa 阻断剂的基于结构的设计:解决 FXIIIa 活性位点中的瞬时疏水袋问题。

凝血因子 XIII(FXIII、F13)由于其在凝血酶凝血级联下游的独特位置,被认为是降低出血风险的抗凝药物的一个有前景的靶标。然而,到目前为止,还没有针对 FXIII 的有效药物,甚至还没有化合物进入临床试验。2013年,我们发表了活性状态下FXIII的共晶结构(FXIIIa°),从而为合理设计有效的FXIIIa阻滞剂提供了活性位点的详细图谱。在这里,我们首次报告了一种基于结构的方法来提高 FXIIIa 抑制剂的亲和力。FXIII 与甲基噻唑部分复合结晶,以解决靠近催化中心的新型瞬时疏水袋。通过随后基于结构的设计合理化乙酯的引入,与母体先导化合物相比,抑制剂的效力显着提高。这里描述的疏水口袋的占据可能是开发有效的可逆且口服的 FXIIIa 阻滞剂的关键一步。
更新日期:2020-03-17
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