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Are StarDrop’s P450 models QSAR models?

Tuesday, 29 September 2009 21:39
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Matt Segall

No. The P450 models differ from the QSAR models, being based on simulation of the chemical reaction mechanisms which lead to the formation of metabolites. Although experimental data are used to tune the parameters of the model and validate the results, the form of the underlying model is not based on an empirical fit to a training data set and this gives greater transferability across a wide range of chemistry without loss of accuracy. Accurate modeling of the chemical reactions requires quantum mechanical simulations, which are much more computationally expensive than the descriptor calculations employed by QSAR models. Consequently, the P450 metabolism models are significantly slower, taking a couple of minutes per compound. However, identifying the most likely cause of metabolic instability for a compound can help to guide chemical modifications aimed at reducing the vulnerability.


How does StarDrop calculate quantum mechanical reaction energies for the P450 models?

Tuesday, 29 September 2009 21:38
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administrator

We use an adapted version of MOPAC97 employing the AM1 method. As a semi-empirical method, AM1 is known to exhibit some systematic errors. Therefore, post hoc corrections are applied which have been derived from extensive ab initio calculations.


How are 3D geometries generated within the P450 models?

Tuesday, 29 September 2009 21:38
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administrator

Initial 3D geometries are generated using Corina (developed by Molecular Networks) and these are then optimised further within MOPAC97. Unconstrained geometries are used, as experimental analysis has shown that the results are relatively insensitive to the geometry provided a good local minimum is used.


Can we use CSL values in a Scoring Profile?

Tuesday, 29 September 2009 21:38
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Ed Champness

Yes, the Composite Site Lability (CSL) values are reported with an uncertainty in prediction and can be used in a Scoring Profile.


Can you predict the metabolic rate?

Tuesday, 29 September 2009 21:37
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Matt Segall

In addition to the vulnerability of individual sites on a molecule, whether a compound is metabolised, and the overall rate of metabolism, will depend upon many factors in the P450 catalytic cycle, including the affinity of the molecule for the enzyme, the rates of reduction and rates of decoupling via peroxide formation. These are currently unknowns and hence metabolic rate, as opposed to lability, cannot be predicted in general. However, for individual chemical series typically only a small number of these factors dictate the rate of product formation. In this case it is possible to build local models, using the Composite Site Lability (CSL) as a descriptor.


Can these P450 models tell us which isoform is responsible for metabolism of a compound?

Tuesday, 29 September 2009 21:37
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administrator

No, these models do not predict the most likely isoform responsible for metabolism.


How accurate are the P450 models?

Tuesday, 29 September 2009 21:30
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Matt Segall

The accuracies of the models for each isoform when tested on independent test sets are shown below:

Results of the P450 Regioselectivity Models on independent test sets

Isoform N * Top-2** Top-3** All Top-3
CYP3A4 352 84.5% 90.5% 53.6%
CYP2D6 221 91.1% 92.9% 71.4%
CYP2C9 222 85.7% 93.9% 75.5%
CYP1A2 238 87.7% 89.5% 64.9%
CYP2C8 114 81.5% 92.6% 70.4%
CYP2C19 213 85.7% 89.8% 69.4%
CYP2E1 134 90% 93.3% 80%

* N = number of compounds in independent test set.
** Observed metabolites in the top 2/3 predicted sites






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