Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450 Export

@article{citeulike:4146263, abstract = {doi: 10.1021/ct700313j We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software.}, author = {Rydberg, Patrik and Hansen, Sine M. and Kongsted, Jacob and Norrby, Per-Ola and Olsen, Lars and Ryde, Ulf}, citeulike-article-id = {4146263}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/ct700313j}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/ct700313j}, day = {1}, doi = {10.1021/ct700313j}, journal = {Journal of Chemical Theory and Computation}, keywords = {in, incorporate, to, try, work, your}, month = {April}, number = {4}, pages = {673--681}, posted-at = {2009-03-07 11:34:55}, priority = {0}, title = {Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450}, url = {http://dx.doi.org/10.1021/ct700313j}, volume = {4}, year = {2008} }

TY - JOUR ID - citeulike:4146263 L3 - citeulike-article-id:4146263 N2 - doi: 10.1021/ct700313j We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software. IS - 4 JF - Journal of Chemical Theory and Computation EP - 681 TI - Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450 VL - 4 SP - 673 KW - in KW - incorporate KW - to KW - try KW - work KW - your AU - Rydberg, Patrik AU - Hansen, Sine AU - Kongsted, Jacob AU - Norrby, Per-Ola AU - Olsen, Lars AU - Ryde, Ulf PY - 2008/04/01/ UR - http://dx.doi.org/10.1021/ct700313j ER -