%0 Journal Article %1 RN244 %A Celis-Barros, C. %A Saavedra-Rivas, L. %A Salgado, J.C. %A Cassels, B.K. %A Zapata-Torres, G. %D 2015 %J Journal of Computer-Aided Molecular Design %K atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, dqcauchile drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation, %N 1 %P 37-46 %R 10.1007/s10822-014-9802-7 %T Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition %U /brokenurl#<Go to ISI>://WOS:000346913200004 %V 29 %X 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.

@article{RN244, 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.}, added-at = {2019-12-04T03:57:35.000+0100}, author = {Celis-Barros, C. and Saavedra-Rivas, L. and Salgado, J.C. and Cassels, B.K. and Zapata-Torres, G.}, biburl = {https://www.bibsonomy.org/bibtex/22915f93f3501249d433fc09841d892a0/dqcauchile}, doi = {10.1007/s10822-014-9802-7}, interhash = {e783781d34b68f8ff5590f6f87f9d63c}, intrahash = {2915f93f3501249d433fc09841d892a0}, issn = {0920-654x}, journal = {Journal of Computer-Aided Molecular Design}, keywords = {atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, dqcauchile drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation,}, number = 1, pages = {37-46}, timestamp = {2019-12-04T03:58:17.000+0100}, title = {Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition}, type = {Journal Article}, url = {/brokenurl#<Go to ISI>://WOS:000346913200004}, volume = 29, year = 2015 }