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Structure‐Based Design of FXIIIa‐Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa
Author(s) -
Stieler Martin,
Büchold Christian,
Schmitt Marisa,
Heine Andreas,
Hils Martin,
Pasternack Ralf,
Klebe Gerhard
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000056
Subject(s) - chemistry , moiety , discovery and development of direct thrombin inhibitors , active site , thrombin , pharmacology , stereochemistry , combinatorial chemistry , medicine , biochemistry , enzyme , platelet
Abstract 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.