IChem:AVersatile Toolkit for Detecting, Comparing, and Predicting Protein-Ligand Interactions

International audienceStructure-based ligand design requires an exact description of the topology of molecular entitiesu nder scrutiny.I Chem is a softwarep ackage that reflects the many contributions of our research group in this area over the last decade. It facilitates and automates many tasks (e.g.,l igand/cofactor atom typing, identification of key water molecules) usually left to the model-er's choice. It therefore permits the detection of molecular interactions between two molecules in av ery precise and flexible manner.M oreover,I Chem enables the conversion of intricate three-dimensional (3D) molecular objectsi ntos imple representations (fingerprints, graphs) that facilitate knowledge ac-quisitiona tv ery high throughput.T he toolkiti sa ni deal companion for setting up and performing many structure-based designc omputations

Structural analysis of protein/ligand complexes and its applications in chemogenomics

Comprendre les interactions réalisées entre un candidat médicament et sa protéine cible est un enjeu crucial pour orienter la recherche de nouvelles molécules. En effet, ce processus implique de nombreux paramètres qu’il est nécessaire d’analyser séparément pour mieux comprendre leurs effets.Nous proposons ici deux nouvelles approches observant les relations protéine/ligand. La première se concentre sur la comparaison de cavités formées par les sites de liaison pouvant accueillir une molécule. Cette méthode permet d’inférer la fonction d’une protéine mais surtout de prédire « l’accessibilité » d’un site de liaison pour un médicament. La seconde tactique se focalise sur la comparaison des interactions non-covalentes réalisées entre la protéine et le ligand afin d’améliorer la sélection de molécules potentiellement actives lors de criblages virtuels, et de rechercher de nouveaux fragments moléculaires, structuralement différents mais partageant le même mode d’interaction.Understanding the interactions between a drug and its target protein is crucial in order to guide drug discovery. Indeed, this process involves many parameters that need to be analyzed separately to better understand their effects.We propose two new approaches to observe protein/ligand relationships. The first focuses on the comparison of cavities formed by binding sites that can accommodate a small molecule. This method allows to infer the function of a protein but also to predict the accessibility of a binding site for a drug. The second method focuses on the comparison of non-covalent interactions made between the protein and the ligand to improve the selection of potentially active molecules in virtual screening, and to find new molecular fragments, structurally different but sharing the same mode of interaction

L'analyse structurale de complexes protéine/ligand et ses applications en chémogénomique

Understanding the interactions between a drug and its target protein is crucial in order to guide drug discovery. Indeed, this process involves many parameters that need to be analyzed separately to better understand their effects.We propose two new approaches to observe protein/ligand relationships. The first focuses on the comparison of cavities formed by binding sites that can accommodate a small molecule. This method allows to infer the function of a protein but also to predict the accessibility of a binding site for a drug. The second method focuses on the comparison of non-covalent interactions made between the protein and the ligand to improve the selection of potentially active molecules in virtual screening, and to find new molecular fragments, structurally different but sharing the same mode of interaction.Comprendre les interactions réalisées entre un candidat médicament et sa protéine cible est un enjeu crucial pour orienter la recherche de nouvelles molécules. En effet, ce processus implique de nombreux paramètres qu’il est nécessaire d’analyser séparément pour mieux comprendre leurs effets.Nous proposons ici deux nouvelles approches observant les relations protéine/ligand. La première se concentre sur la comparaison de cavités formées par les sites de liaison pouvant accueillir une molécule. Cette méthode permet d’inférer la fonction d’une protéine mais surtout de prédire « l’accessibilité » d’un site de liaison pour un médicament. La seconde tactique se focalise sur la comparaison des interactions non-covalentes réalisées entre la protéine et le ligand afin d’améliorer la sélection de molécules potentiellement actives lors de criblages virtuels, et de rechercher de nouveaux fragments moléculaires, structuralement différents mais partageant le même mode d’interaction

L'analyse structurale de complexes protéine/ligand et ses applications en chémogénomique

Comprendre les interactions réalisées entre un candidat médicament et sa protéine cible est un enjeu crucial pour orienter la recherche de nouvelles molécules. En effet, ce processus implique de nombreux paramètres qu il est nécessaire d analyser séparément pour mieux comprendre leurs effets.Nous proposons ici deux nouvelles approches observant les relations protéine/ligand. La première se concentre sur la comparaison de cavités formées par les sites de liaison pouvant accueillir une molécule. Cette méthode permet d inférer la fonction d une protéine mais surtout de prédire l accessibilité d un site de liaison pour un médicament. La seconde tactique se focalise sur la comparaison des interactions non-covalentes réalisées entre la protéine et le ligand afin d améliorer la sélection de molécules potentiellement actives lors de criblages virtuels, et de rechercher de nouveaux fragments moléculaires, structuralement différents mais partageant le même mode d interaction.Understanding the interactions between a drug and its target protein is crucial in order to guide drug discovery. Indeed, this process involves many parameters that need to be analyzed separately to better understand their effects.We propose two new approaches to observe protein/ligand relationships. The first focuses on the comparison of cavities formed by binding sites that can accommodate a small molecule. This method allows to infer the function of a protein but also to predict the accessibility of a binding site for a drug. The second method focuses on the comparison of non-covalent interactions made between the protein and the ligand to improve the selection of potentially active molecules in virtual screening, and to find new molecular fragments, structurally different but sharing the same mode of interaction.STRASBOURG-Bib.electronique 063 (674829902) / SudocSudocFranceF

New J Chem New J Chem

Bis(1,2-4 triazin-3-yl)pyridines "BTPs'' represent a new class of N-donor extracting agents that separate trivalent actinides and lanthanides from nuclear waste solutions with high An/Ln separation factors. We report here QM calculations on the effect of R-para-BTP substituents on the protonation and complexation energies of these ligands (1 : 1 and 1 : 3 complexes with Ln(III) lanthanides) in the gas phase. Both processes follow similar trends and are highly sensitive to the electron donor/acceptor character and polarizability of R. When compared to R-pyr analogues with pyridine, R-BTPs are found to be intrinsically much more basic, by ca. 20 kcal mol(-1). In aqueous solution, however (modelled by the continuum PCM model), BTPs and pyridines have a similar basicity, pointing to the importance of solvent environment on their protonation states. In the optimized Ln(R-BTP)(3)(3+) complexes with Ln = La, Eu, Yb, complexation energies E-c3 increase with the intrinsic basicity of the ligands, in the order R = NMe2 > NH2 > OMe > C6H5 > (t)Butyl > Me > H > F > Cl. Furthermore, comparison of complexes with different Ln(III) cations indicates that their stability increases in the order La-III < Eu-III < Yb-III, by the same amount with the different R-substituents. The relative contributions of central pyridinyl and lateral triazinyl nitrogens of BTPs are shown to depend on the stoichiometry of the complex and on the Ln(III) size, possibly contributing to the subtle An(III)/Ln(III) discrimination by substituted BTPs.697lp Times Cited:18 Cited References Count:4