194491-44-6Relevant articles and documents
Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies
Ye, Jiqing,Yang, Xiao,Xu, Min,Chan, Paul Kay-sheung,Ma, Cong
supporting information, (2019/09/06)
The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
Molecular recognition at the active site of factor Xa: Cation-π Interactions, stacking on planar peptide surfaces, and replacement of structural water
Salonen, Laura M.,Holland, Mareike C.,Kaib, Philip S. J.,Haap, Wolfgang,Benz, J?rg,Mary, Jean-Luc,Kuster, Olivier,Schweizer, W. Bernd,Banner, David W.,Diederich, Fran?ois
supporting information; experimental part, p. 213 - 222 (2012/03/09)
Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cation-π interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structure-activity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to Ki=2nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes. Factor Xa is an ideal enzyme to undertake molecular recognition studies at atomic level resolution as its active site is completely conserved in complexes with designed ligands. Cation-π interactions, water replacements, and stacking interactions with flat peptide fragments were investigated, revealing large changes in binding affinity resulting from single-atom mutations or positional shifts of heteroatoms in the ligands. Copyright
