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Fragment‐Based De Novo Design Reveals a Small‐Molecule Inhibitor of Helicobacter Pylori HtrA 下载免费PDF全文
Thomas P. Schmidt Dr. Manja Böhm Katharina Stutz Daniel Reker Dr. Bernhard Pfeiffer Prof. Dr. Karl‐Heinz Altmann Prof. Dr. Steffen Backert Prof. Dr. Silja Wessler Prof. Dr. Gisbert Schneider 《Angewandte Chemie (International ed. in English)》2015,54(35):10244-10248
Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity. 相似文献
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Reliable determination of protein-protein interaction sites is of critical importance for structure-based design of small molecules modulating protein function through macromolecular interfaces. We present an alignment-free computational method for prediction of protein-protein interface residues. The method ("iPred") is based on a knowledge-based scoring function adapted from the field of protein folding and small molecule docking. Based on a training set of 394 hetero-dimeric proteins iPred achieves sustained accuracy on an external unbound test set. Prediction robustness was assessed from more than 1500 diverse complexes containing homo- and hetero-dimers. The technique does not rely on sequence conservation, so that rapid interface identification is possible even for proteins for which homologs are unknown or lack conserved residue patterns in interface region. Functional "hot-spot" residues are enriched among the predicted interface residues, rendering the method predestined for macromolecular binding site identification and drug design studies aiming at modulating protein-protein interaction that might influence protein function. For a comparative structural model of peptidase HtrA from Helicobacter pylori, we performed mutation studies for predicted hot-spot residues, which were confirmed as functionally relevant for HtrA activity or oligomerization. 相似文献
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J. K. Brooks Kazuyuki Saitô JD Maitland Wright 《Rendiconti del Circolo Matematico di Palermo》2003,52(1):5-14
LetA be aC*-algebra with second dualA″. Let (φ
n)(n=1,...) be a sequence in the dual ofA such that limφ
n(a) exists for eacha εA. In general, this does not imply that limφ
n(x) exists for eachx εA″. But if limφ
n(p) exists whenever p is the range projection of a positive self-adjoint element of the unit ball ofA, then it is shown that limφ
n(x) does exist for eachx inA″. This is a non-commutative generalisation of a celebrated theorem of Dieudonné. A new proof of Dieudonné’s theorem, for
positive measures, is given here. The proof of the main result makes use of Dieudonné’s original theorem. 相似文献
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Larrabee JA Leung CH Moore RL Thamrong-nawasawat T Wessler BS 《Journal of the American Chemical Society》2004,126(39):12316-12324
Equilibrium dialysis of methionyl aminopeptidase from Escherichia coli (EcMetAP) monitored by atomic absorption spectrometry and magnetic circular dichroism (MCD) shows that the enzyme binds up to 1.1 +/- 0.1 equiv of Co(2+) in the metal concentration range likely to be found in vivo. The dissociation constant, K(d), is estimated to be between 2.5 and 4.0 microM. Analysis of the temperature and magnetization behavior of the two major peaks in the MCD spectrum at 495 and 567 nm suggests that these transitions arise from Co(2+) with different ground states. Ligand field calculations using AOMX are used to assign the 495 nm peak to Co(2+) in the 6-coordinate binding site and the 567 nm peak to Co(2+) in the 5-coordinate site. This is further supported by the fact that the binding affinity of the Co(2+) associated with the 567 nm peak is enhanced when the pH is increased from 7.5 to 9.0, consistent with having an imidazole ligand from a histidine amino acid residue. On the basis of the MCD intensities, it is estimated that, when the 5-coordinate site is fully occupied, 0.1 equiv of cobalt is in the 6-coordinate site. Even when the cobalt concentration is very low, there is a small fraction of binuclear sites in EcMetAP formed through cooperative binding between the 5- and 6-coordinate Co(2+) ions. The magnetization behavior of the 6-coordinate Co(2+) MCD peak is consistent with an isolated pseudo-Kramer doublet ground state, suggesting that the cobalt ions in the binuclear sites are not magnetically coupled. 相似文献
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The eigen frequencies of radial pulsations of neutron stars are calculated in a strong magnetic field. At low densities we
use the magnetic BPS equation of state (EOS) similar to that obtained by Lai and Shapiro while at high densities the EOS obtained
from the relativistic nuclear mean field theory is taken and extended to include strong magnetic field. It is found that magnetized
neutron stars support higher maximum mass whereas the effect of magnetic field on radial stability for observed neutron star
masses is minimal. 相似文献
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Smith TE Kuo WH Balskus EP Bock VD Roizen JL Theberge AB Carroll KA Kurihara T Wessler JD 《The Journal of organic chemistry》2008,73(1):142-150
An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond. 相似文献