| 1. |
- Rydberg, Patrik, et al.
(författare)
-
General transition-state force field for cytochrome p450 Hydroxylation
- 2007
-
Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 3:5, s. 1765-1773
-
Tidskriftsartikel (refereegranskat)abstract
- We have developed force-field parameters for the hydrogen-abstraction transition state of aliphatic hydroxylation by cytochrome P450 using the Q2MM approach. The parametrization is based on quantum chemical (B3LYP) transition-state structures and Hessian matrices for 24 diverse substrate models (14 in the training set and 10 in the test set). The force field is intended to be applicable to any druglike molecule by the use of the general Amber force field (GAFF) for the substrates. The parameters reproduce the geometries within 0.1 angstrom and 1.2 degrees for bond lengths and angles, respectively, with no significant differences between the training and test sets. The Hessian matrix is also well reproduced with a correlation coefficient of 0.99. The parametrization is performed by the ideal iterative approach of Norrby and Liljefors, which we have implemented for the Amber software.
|
|
| 2. |
- Rydberg, Patrik, et al.
(författare)
-
Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450
- 2008
-
Ingår i: J.Chem.Theory Comput.. - : American Chemical Society (ACS). ; 4, s. 673-681
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
