Institute Quimica Organica IQOG CSIC

San Juan de la Rambla, Spain

Institute Quimica Organica IQOG CSIC

San Juan de la Rambla, Spain

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Jimenez-Moreno E.,Institute Quimica Organica IQOG CSIC | Montalvillo-Jimenez L.,Institute Quimica Organica IQOG CSIC | Santana A.G.,Institute Quimica Organica IQOG CSIC | Gomez A.M.,Institute Quimica Organica IQOG CSIC | And 11 more authors.
Journal of the American Chemical Society | Year: 2016

Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition. © 2016 American Chemical Society.


Jimenez-Moreno E.,Institute Quimica Organica IQOG CSIC | Jimenez-Oses G.,University of La Rioja | Jimenez-Oses G.,University of Zaragoza | Gomez A.M.,Institute Quimica Organica IQOG CSIC | And 7 more authors.
Chemical Science | Year: 2015

CH/π interactions play a key role in a large variety of molecular recognition processes of biological relevance. However, their origins and structural determinants in water remain poorly understood. In order to improve our comprehension of these important interaction modes, we have performed a quantitative experimental analysis of a large data set comprising 117 chemically diverse carbohydrate/aromatic stacking complexes, prepared through a dynamic combinatorial approach recently developed by our group. The obtained free energies provide a detailed picture of the structure-stability relationships that govern the association process, opening the door to the rational design of improved carbohydrate-based ligands or carbohydrate receptors. Moreover, this experimental data set, supported by quantum mechanical calculations, has contributed to the understanding of the main driving forces that promote complex formation, underlining the key role played by coulombic and solvophobic forces on the stabilization of these complexes. This represents the most quantitative and extensive experimental study reported so far for CH/π complexes in water. © The Royal Society of Chemistry.


Santana A.G.,Institute Quimica Organica IQOG CSIC | Jimenez-Moreno E.,Institute Quimica Organica IQOG CSIC | Gomez A.M.,Institute Quimica Organica IQOG CSIC | Corzana F.,University of La Rioja | And 4 more authors.
Journal of the American Chemical Society | Year: 2013

A dynamical combinatorial approach for the study of weak carbohydrate/aromatic interactions is presented. This methodology has been employed to dissect the subtle structure-stability relationships that govern facial selectivity in these supramolecular complexes. © 2013 American Chemical Society.


PubMed | CSIC - Biological Research Center, Institute Quimica Organica IQOG CSIC, CSIC - Institute of Physical Chemistry "Rocasolano" and University of La Rioja
Type: Journal Article | Journal: Journal of the American Chemical Society | Year: 2016

Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition.

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