**3. Results**

To evaluate the DDIs prediction accuracy, the IAP (Invariant Accuracy of Prediction) values were calculated using leave-one-out cross-validation procedures (LOO CV). The IAP criterion is numerically equivalent to the AUC ROC (Area Under Curve of the Receiver

Operating Characteristic) [19]. The IAP value is a sample estimate of the probability randomly selected from an independent test set that will correctly classify positive and negative examples. The accuracy of the prediction of DDIs caused by different isoforms of cytochrome P450 is presented in Table 2.

**Table 2.** Accuracy of the DDIs prediction.


The developed models showed good accuracy varying from 0.82 (for CYP2C19 DDIs) to 0.98 (for CYP2C8 DDIs) with an average IAP of about 0.92. It is essential that the accuracy for DDIs mediated by CYP3A4 is high (0.93) because interactions on the level CYP3A4 can cause severe DDIs that must be detected and avoided during the investigation of new drugs. Thus, the accuracy of SAR models is adequate to use this method for practical tasks of drug discovery and development.

The models created are freely available via the Internet on the Way2Drug.com web portal on the DDIs web-service [20] that allows for the prediction of various DDIs parameters and does not require registration or log-in. The combinations of warfarin taken regularly (widely used anticoagulant with narrow therapeutic index) with various nonsteroidal antiinflammatory drugs (NSAIDs) are common and can increase the risk of gastrointestinal bleeding [21]. As an example for illustrating the web-service analysis, the potential DDI for a pair of warfarin and naproxen (one of the commonly used NSAIDs) was predicted (see Figure 2).

**Figure 2.** DDI prediction for warfarin and naproxen performed using the web service [20].

The results of the prediction displayed in the block "Prediction of DDIs mediated by P450 (PASS double mol) (7 CYP)" show that the maximum Δ *P* value (0.364) was calculated for cytochrome P450 CYP2C9 (see Table 3). Therefore, the DDI for warfarin and naproxen is most likely to occur at the level of biotransformation carried out by cytochrome P450 CYP2C9.



Negative Δ*P* values for the other six isoforms of cytochrome P450 indicate that these enzymes are not involved in DDIs at the level of warfarin and naproxen biotransformation.
