Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• -based probe derived from 1 was used to identify mammalian cathepsin B as a potentially important off-target of 1 and 4. Computational docking studies and the evaluation of truncated analogues of 4 reveal structural determinants for TcCYP51 binding, information that will be useful in further optimization

• hypothesis that the 4-pyridyl ring in 4 is involved in binding TcCYP51. The 2-pyridyl ring system in 3 is presumably unable to chelate heme in TcCYP51 due to steric hindrance from the immediately adjacent amide linkage. Computational docking studies We next employed computational docking and a model derived

Synthesis and in silico screening of a library of β-carboline-containing compounds

• Kay M. Brummond,
• John R. Goodell,
• Matthew G. LaPorte,
• Lirong Wang and
• Xiang-Qun Xie

Beilstein J. Org. Chem. 2012, 8, 1048–1058, doi:10.3762/bjoc.8.117

• predict potential targets of the newly synthesized library of β-carboline-containing compounds. High-throughput docking studies for protein-target prediction of newly synthesized compounds Molecular docking studies were performed with the 34 newly synthesized compounds, represented by scaffolds 1, 2, 3

An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells

• Grazia Marano,
• Claas Gronewold,
• Martin Frank,
• Anette Merling,
• Christian Kliem,
• Sandra Sauer,
• Manfred Wiessler,
• Eva Frei and
• Reinhard Schwartz-Albiez

Beilstein J. Org. Chem. 2012, 8, 787–803, doi:10.3762/bjoc.8.89

• upon binding of cells to fibronectin or fibrinogen. However, GSF, which inhibits cell adhesion to both ECM-proteins, inhibits the cleavage of the MMP-2 pro-sequence. A GSF–αvβ3 interaction could directly or allosterically inhibit binding of pro-MMP-2 to the integrin, and our in silico blind-docking

• studies (Figure 4) have shown GSF to bind to another domain on αvβ3 in addition to the RGD binding site. Alternatively, GSF could bind to the ECM and thereby inhibit cell adhesion and MMP-2 activation. The lack of inhibition of cell adhesion to plastic by GSF points to such a mechanism. A reduction of the

En route to photoaffinity labeling of the bacterial lectin FimH

• Thisbe K. Lindhorst,
• Michaela Märten,
• Andreas Fuchs and
• Stefan D. Knight

Beilstein J. Org. Chem. 2010, 6, 810–822, doi:10.3762/bjoc.6.91

• photoactive mannosides 1, 2, 3, and 5, we have performed computer-aided docking studies using FlexX [17][18][19] to get an idea about their binding to the bacterial lectin FimH, as reported earlier [20]. FlexX produces so-called scoring values for each docked ligand, which can be regarded as a rough estimate

• -labeling of the bacterial lectin FimH. The target molecules 12 and 13 were selected after docking studies based on the structure of FimH and according to binding studies employing type 1-fimbriated E. coli. Photo-crosslinking was tested with the model peptide angiotensin II and the regiochemistry of the

• residues on FimH, according to the photoaffinity methodology. However, so far we have not been successful in an unequivocal mass-spectrometric analysis of any proteolytic digest, we have obtained so far. Thus, this study is currently continued in our laboratory. Experimental Docking studies Computer-aided

A bivalent glycopeptide to target two putative carbohydrate binding sites on FimH

• Thisbe K. Lindhorst,
• Kathrin Bruegge,
• Andreas Fuchs and
• Oliver Sperling

Beilstein J. Org. Chem. 2010, 6, 801–809, doi:10.3762/bjoc.6.90

• lectin domain was probed by computational docking studies [16]. Three new potential carbohydrate binding cavities on the surface of the FimH lectin domain, in addition to the mannose pocket at the tip of the domain, were identified which have a marked preference for the same subset of high-mannose

• regulation of the ligand-receptor interaction. Experimental Docking studies Computer-aided modeling to estimate the spacer lengths of a bivalent glycopeptide ligand to allow bridging of two putative binding sites on FimH was carried out using FlexX flexible docking and consensus scoring, implemented in Sybyl

• extended area on the protein. b) Docking studies were used to estimate the length of a linker that is required to bridge the putative two binding sites. The bivalent glycopeptide 1 is the target molecule to test the hypothesis of two carbohydrate binding sites on FimH. Its retrosynthesis delivers the azido