357
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
PASS prediction results, which is based on the knowledgebase of “mechanism-effect” relationships) [45]. The current version of PASS predicts the biological activity spectrum, including molecular mechanisms of action, pharmacological effects
and toxicity, interaction of compounds with transport proteins and drug metabolizing enzymes. Analysis of the biological activity spectrum prediction allows identifying potential pharmacokinetic and pharmacodynamic drug interactions by PharmaExpert. Pharmacokinetic interactions are detected based on prediction results
of compounds interactions with drug metabolizing enzymes and transport proteins
involved in absorption, distribution and excretion. Pharmacodynamic interactions
are identified based on analysis of prediction results for the molecular mechanisms
of action, pharmacological effects and toxicity. Overall flowchart identification of
pharmacokinetic drug interactions is shown in Fig. 11.1.
The algorithm of the pharmacokinetic drug interaction identification is based on
comparison of biological activity spectra in compounds (in the block diagram they
are labeled as Compound 1 and Compound 2), predicted by PASS. It is necessary to
determinate whether compounds are predicted as substrates of the same transporter
Fig. 11.1 Overall flowchart identification of pharmacokinetic drug interactions
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
PASS prediction results, which is based on the knowledgebase of “mechanism-effect” relationships) [45]. The current version of PASS predicts the biological activity spectrum, including molecular mechanisms of action, pharmacological effects
and toxicity, interaction of compounds with transport proteins and drug metabolizing enzymes. Analysis of the biological activity spectrum prediction allows identifying potential pharmacokinetic and pharmacodynamic drug interactions by PharmaExpert. Pharmacokinetic interactions are detected based on prediction results
of compounds interactions with drug metabolizing enzymes and transport proteins
involved in absorption, distribution and excretion. Pharmacodynamic interactions
are identified based on analysis of prediction results for the molecular mechanisms
of action, pharmacological effects and toxicity. Overall flowchart identification of
pharmacokinetic drug interactions is shown in Fig. 11.1.
The algorithm of the pharmacokinetic drug interaction identification is based on
comparison of biological activity spectra in compounds (in the block diagram they
are labeled as Compound 1 and Compound 2), predicted by PASS. It is necessary to
determinate whether compounds are predicted as substrates of the same transporter
Fig. 11.1 Overall flowchart identification of pharmacokinetic drug interactions