Stefan G. Krimmer

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Water is ubiquitously present in any biological system and has therefore to be regarded as an additional binding partner in the protein-ligand binding process. Upon complex formation, a new solvent-exposed surface is generated and water molecules from the first solvation layer will arrange around this newly formed surface. So far, the influence of such(More)
Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it(More)
Drug binding involves changes of the local water structure around proteins including water rearrangements across surface-solvation layers around protein and ligand portions exposed to the newly formed complex surface. For a series of thermolysin-binding phosphonamidates, we discovered that variations of the partly exposed P2'-substituents modulate binding(More)
Amphiphilic block copolymers based on HPMA and ε-CL were synthesized by ring-opening polymerization of ε-CL followed by RAFT polymerization of HPMA. A copolymer composed of 34 kDa PHPMA and 8.5 kDa PCL associated into micelles with CMC of 5.4 µg · mL(-1) . A novel retinoid, 3-Cl-AHPC-OMe, was incorporated into micelles with 25 wt.-% loading by dialysis(More)
Fragment-based lead discovery (FBLD) has become a pillar in drug development. Typical applications of this method comprise at least two biophysical screens as prefilter and a follow-up crystallographic experiment on a subset of fragments. Clearly, structural information is pivotal in FBLD, but a key question is whether such a screening cascade strategy will(More)
A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing(More)
In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization(More)
Successful optimization of a given lead scaffold requires thorough binding-site mapping of the target protein particular in regions remote from the catalytic center where high conservation across protein families is given. We screened a 361-entry fragment library for binding to the aspartic protease endothiapepsin by crystallography. This enzyme is(More)
Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding(More)
For a conscientious interpretation of thermodynamic parameters (Gibbs free energy, enthalpy and entropy) obtained by isothermal titration calorimetry (ITC), it is necessary to first evaluate the experimental setup and conditions at which the data were measured. The data quality must be assessed and the precision and accuracy of the measured parameters must(More)