2015 |
Celis-Barros, C; Saavedra-Rivas, L; Salgado, J C; Cassels, B K; Zapata-Torres, G Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition Artículo de revista Journal of Computer-Aided Molecular Design, 29 (1), pp. 37-46, 2015, ISSN: 0920-654x. Resumen | Enlaces | BibTeX | Etiquetas: atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation @article{RN244, title = {Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition}, author = { C. Celis-Barros and L. Saavedra-Rivas and J.C. Salgado and B.K. Cassels and G. Zapata-Torres}, url = {/brokenurl#<Go to ISI>://WOS:000346913200004}, doi = {10.1007/s10822-014-9802-7}, issn = {0920-654x}, year = {2015}, date = {2015-01-01}, journal = {Journal of Computer-Aided Molecular Design}, volume = {29}, number = {1}, pages = {37-46}, abstract = {A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I > Br > Cl, in agreement with the IC50 values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C-X center dot center dot center dot O angle is about 170A degrees; and the X center dot center dot center dot O=C angle approaches 120A degrees, as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors' halogen-bonding phenyl ring, indicating that the electron withdrawing group enlarges the sigma-hole, resulting in improved halogen bonding properties.}, keywords = {atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation}, pubstate = {published}, tppubtype = {article} } A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I > Br > Cl, in agreement with the IC50 values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C-X center dot center dot center dot O angle is about 170A degrees; and the X center dot center dot center dot O=C angle approaches 120A degrees, as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors' halogen-bonding phenyl ring, indicating that the electron withdrawing group enlarges the sigma-hole, resulting in improved halogen bonding properties. |
2015 |
Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition Artículo de revista Journal of Computer-Aided Molecular Design, 29 (1), pp. 37-46, 2015, ISSN: 0920-654x. |