The Keys to Making Good Models from Chemical Structures

Authors: Jones J
Software: ADMET Predictor®
Division: Simulations Plus

There are many different things that make a model “good.” Building one is very much a multi-objective problem—actually, it is a multi-objective process. This is especially true for the kind of global models we distribute with ADMET Predictor. In this blog post, I will focus more on what you should look for—and look out for—in models built by someone else. Many are things to keep in mind when evaluating software, especially when running comparisons.


Good Structures

Models are built and trained on large data sets, but that doesn’t mean sheer quantity is what you should look for. The old adage applies: Garbage in, garbage out.

We spend a lot of time correcting chemical structures in data sets taken from the literature, especially when they come from compilations or some other secondary source (in fact, we usually avoid using any compilation where we are not able to trace a data point back to the original publication).

Sometimes errors are simply a matter of stereochemistry. Mismatches between names and structures are common, especially for metabolites. Incorrect structural isomers are also a problem, most often as relates to compounds being drawn as unrepresentative tautomers, which can cause large predictive errors in some cases.

We take pains to train models on dominant tautomers or, where it isn’t possible to make that determination unambiguously, reasonably representative ones. The tautomer standardization tool is a good way to do this. Running it on your own data before calculating ADMET properties is a good idea to ensure that all of your chemical structures are accurate.


Good Endpoint Data

For local models, consistency is king: if at all possible, all of your data should come from a single laboratory over a short time period. Barring that, the assay conditions should be as consistent as possible. This does reduce the noise in the data, but it will not be possible to tell how robust your predictions are to small deviations in protocol.

When building a global model, it is wise to get data from at least two sources, and preferably more. The need to check for consistency in results puts a premium on having reference in common. This is especially true when some data transform is necessary to get endpoint values on a common scale—e.g., converting IC50 to Ki. Redundancy in the data actually used to build a model is undesirable, but redundant observations within “raw” data sets and between labs are good because they provide a way to measure how much underlying noise there is in the data. When evaluating a model built by someone else, make sure you can identify the source of the data and details about how the datasets were merged.


Broad Applicability Domains

To be useful, a model must have a well-defined “applicability domain,” i.e., a way to determine whether a new compound lies within the chemical space over which the model is reasonably valid. This is especially true when regulatory issues are involved and for non-linear models, which tend to extrapolate poorly.

Applicability domains for our ANNE models are defined by hypercubes in the model’s standardized space: the range of training set values for each descriptor used in the model is mapped to the interval [0,1]. A compound for which any of those descriptors is below -0.1 or above 1.1 is flagged as “out of scope”—i.e., as lying outside the applicability domain of the model. The prediction for such a compound may be correct but it would be unwise to put much faith in it.

Models for which applicability domains are not well-defined should be avoided.


Good Descriptors

In general, we favor property-based descriptors derived from atomic properties over “constitutional” descriptors based on substructure counts. This preference reflects the desirability of having a broad applicability domain.

Many of the molecular descriptors used in our proprietary models are derived from properties that reflect the interactions of individual atoms with all other atoms in the molecule. This means that interactions between substructures—e.g., in sulfonylated amidines—can be “covered” by interpolation from nitro, cyano, carbonyl and alkyl substituted analogs. A model based solely on constitutive descriptors, on the other hand, will properly classify such a novel compound as “out of scope.”

If the only amidines in a data set bear electron-withdrawing substituents, a prediction for an alkyl analog based solely on constitutive descriptors is likely to be biased even though the compound will not be flagged as “out of scope.” A model based on descriptors derived from atomic properties, in contrast, can be expected to detect that the compound lies outside its applicability domain.

Good external models will provide how many descriptors went into a model, and the best will provide a detailed description of the full menu of descriptors that were available to the model and a descriptor sensitivity analysis for each model, much like we do in ADMET Predictor.


Predictions vs. Table Look-ups

Some ADMET prediction programs are built upon very large compilations of literature data. When presented with a structure for which it already “knows” the answer, such a program can respond in two ways. It can regurgitate the literature value—in which case its “prediction” is likely to be perfect—or it can “hide” the known answer and try to predict it as though it were truly unknown.

Returning a look-up value is preferable when the value itself is what matters, but it is misleading when a person is trying to compare predictive performance. The best way to address this problem is to run evaluations using unpublished results, but that is not always practical. A simple but effective alternative is simply to ignore all predictions that are “too good” (error < 0.05 log units, for example) when compiling performance statistics. If doing so makes a significant difference, you are probably dealing with a look-up model, at least in part.


Protection Against Overtraining

Our models are trained so as to try to maximize their accuracy—i.e., to minimize their error. Usually this is accomplished by minimizing a weighted sum of squared errors. Were that process allowed to go to completion, artificial neural nets (ANNs) and other powerful nonlinear data mining tools models would ultimately produce models with no residual error in predictions for the training set, provided there are no observations with identical descriptors but different response values.

The downside of that precise fitting is that the model will likely be unable to accurately predict endpoints for compounds not actually included in the training set. We protect our ANNs from this risk by testing performance against a companion verification set as part of each cycle of the training process. The error on the training set necessarily decreases or stays the same, but an increase in errors on the verification is a signal that modeling is losing its ability to generalize—i.e., is becoming overfitted. If that continues to be the case over more than a few iterations, the process is stopped “early” and model weights from the stage at which verification performance was optimal is used. The easiest way to see that a model is overtrained is that it performs much better on the training data than the test data.


Unbiased Test Sets

Testing predictive performance on a “held out” test set is the gold standard for validation. We do this by avoiding any opportunity for the dependent variable (endpoint) to bias test set selection. We prefer to use Kohonen mapping or K-means clustering where possible; these stratified sampling techniques examine the data point distribution in the overall descriptor space and generally strike a good balance between making the training pool informative and the test set representative. Neither makes any use of endpoint information in the partitioning process.

When data sets are not amenable to either of these methods, we usually turn to stratified sampling, which ensures that the dependent variable range is evenly sampled. For many ADMET endpoints of interest, good data is limited, which makes data sets small. The noise introduced by random sampling can easily overwhelm the signal in such cases—it is all too easy to get a misleadingly good or an unnecessarily bad partition by chance—so it is generally better to avoid random sampling unless the data set is large (>1000 examples). Once selected, the test set does not participate in the model building process; it is only used to assess the performance of the final ensemble model.

Once again, a good model should provide the details of how the training and test sets were selected, and those methods should conform to the rules described above.


Relevant Performance Statistics

We provide several measures of predictive performance for our models. Classification performance is reported in tabular form as training pool and test set Sensitivity (the fraction of positive examples that are correctly classified by the model); Specificity (the fraction of negatives that are correctly classified); and Concordance (the fraction examples that are correctly classified). The number of positive and negative examples is provided to show how (un)balanced each data set is. The degree of imbalance is important because the data sets used to characterize biological activities are often not themselves representative of the population of compounds to which the model will ultimately be applied—i.e., the “target population.” This is particularly true for classification models, which are often artificially made more evenly balanced between positive and negative examples than the target population is. We focus on optimizing specificity and sensitivity because they are insensitive to imbalances in class size. Concordance is quite sensitive to imbalance; optimizing it increases the risk of seeing qualitatively different performance “in the field” than in the test set. Comparing published concordance (or “accuracy”) statistics obtained using different data sets should be avoided for this reason.

High sensitivity and high specificity are both good, but there is always a trade-off between the two. Most of our models are optimized by maximizing Youden’s index J, where:

J = Sensitivity + Specificity – 1

which represents an equal weighting of the two performance criteria.

Regression performance is reported in the form of predicted vs. observed plots. Separate summary statistics are presented for the training pool and tests sets; the latter is highlighted in the text because it is typically a better indicator of what you can expect for predictions on novel compounds. Statistics include the root mean square error (RMSE) and mean absolute error (MAE). Typically, these are log/log plots, so an RMSE of 0.3 translates to an expected two-fold error range, whereas an RMSE of 0.6 indicates an expected error of about four-fold; the smaller the value, the better the performance.

The slopes and intercepts for the observed vs. predicted regression lines are shown. Perfect agreement between prediction and experiment is indicated by a slope of 1 and an intercept of 0, but it is difficult to assess how meaningful deviations from those values are in any particular case.

The squared Pearson’s correlation coefficient (R2) is also reported for regression models. Statistically speaking, this equals the fraction of the variance in y (the observed value) that is explained by x (the predicted value). This statistic is quite sensitive to the range and distribution of values for the dependent variable, just as concordance is sensitive to the degree of imbalance in a categorical data set. It can be a very misleading statistic for comparing model performance on different data sets. RMSE is much better for that purpose.

We certainly have our favorite performance statistics, but we know that different statisticians may prefer different statistics, which is why we provide such a thorough offering. You should insist that any model you choose to use does the same.


Confidence Estimates for Individual Predictions

We published (Clark 2014) a general methodology for using the degree of consensus between networks in a classification ANNE to accurately estimate the confidence one should have that an individual prediction is correct. This corresponds to the positive and negative predictive value (PPV and NPV) for positive and negative classifications, respectively. Like concordance, confidence estimates are sensitive to the degree of imbalance in a data set. In doing evaluations against internal or published data, you will need to correct expectations for difference in the degree of imbalance.


The Model That Looked Too Good to Be True

In originally developing our respiratory model, we turned to a data set of 80 compounds commonly used to model this endpoint. It consists of 40 sensitizers identified through inhalation studies in rats and 40 of 118 nonsensitizers which were not skin sensitizers (Graham 1997). It has subsequently been shown that 80% of the respiratory sensitizers could be assigned to some mechanistic domain (acylation, Michael addition, Schiff base formation, SN2, or SNAr) by applying simple SMARTS rules to classify the compounds. Using the 79 compounds having structural data, ANN models were built with ADMET Predictor that achieved 100% accuracy using as few as 6 descriptors. Furthermore, a model utilizing five neurons and a single descriptor was developed that achieved ~90% concordance on the training set. Moreover, it was 100% accurate on the external test set of 8 compounds selected by Kohonen mapping. The “magic” descriptor was EqualEta, which has a strong reciprocal correlation with molecular weight. The excessively high performance reflects a high degree of homogeneity within classes (“methyl, ethyl, butyl, futile” syndrome): many of the positives were simple homologous elaborations of each other. As a result, positives that shared a mechanism were similar in size. Any model derived from a “clumpy” data set that small would likely be of little use on any truly external compounds.

Needless to say, we had to expand our data set considerably in order to generate a Sens_Resp model that we deemed useful enough to release. You, too, should beware of any such “perfect” model; it is likely to have a very limited (and misleading) applicability domain and to be too good to be true!

A related problem bedevils academic and commercial CYP models that are built from data sets in which every compound is a substrate for some CYP. This implicitly makes any prediction a contingent one—e.g., “This is my prediction assuming that the compound is a substrate for some CYP.” Such models almost inevitably over-generalize, classifying all large molecules as CYP3A4 substrates, all bases as substrates for CYP2D6, and all weak acids as CYP2C9 substrates. Moreover, they typically also misclassify those substrates that do not match the corresponding rule-of-thumb archetype. We addressed this for our CYP models by supplementing the data set with large molecules and metabolic intermediates which are demonstrably not CYP substrates.

When you evaluate a model, and the performance statistics appear to be “too good to be true,” for instance, a regression model has an RMSE < 0.1, or a classification model has sensitivity and specificity values of >0.98, it would behoove you to dig thoroughly into the details of the model and the data that went into the model. It could be that the model was derived from “clumpy” data, like described above, or it could be a deficiency in any of the issues discussed in this blog.


Choosing Your ADMET Prediction Software

As you can see, there are a myriad of issues to consider when attempting to make accurate in silico ADMET predictions. Having access to large, accurate data sets will always be paramount, but the list of considerations discussed above also play critical roles in prediction performance. At Simulations Plus, we have been working on these issues for over 25 years, and we never stop adding data and trying to improve the accuracy of our predictions. Before you settle on a provider for your ADMET predictions, please take the time to discuss the issues described in this article with each vendor to ensure that they’ve done all that they can to make their models as accurate as possible.

If you’re interested in learning more about ADMET Predictor and our models, you can schedule a demo with one of our experts or request an evaluation license.



Much of this text is taken from the ADMET Predictor manual and was written by Robert Clark with help from the ADMET Predictor team.


Clark RD, Liang W, Lee AC, Lawless MS, Fraczkiewicz R, Waldman M. “Using beta binomials to estimate classification uncertainty for ensemble models.” J Cheminfo 2014, 6:34.

Graham C, Rosenkranz HS, Karol MH. “Structure-Activity Model of Chemicals That Cause Human Respiratory Sensitization.” Reg Toxicol Pharmacol 1997; 26:296-306.