Prediction of Adverse Effects of Drug–Drug Interactions on Cardiovascular System Based on the Analysis of Structure–Activity Relationships

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Vladislav S. Sukhachev^1,a*, Sergey M. Ivanov¹, and Alexander V. Dmitriev¹

¹Institute of Biomedical Chemistry, 119121 Moscow, Russia

^* To whom correspondence should be addressed.

Received February 21, 2023; Revised March 17, 2023; Accepted March 17, 2023

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Co-administration of drugs often leads to drug–drug interactions, which could be accompanied by various adverse drug reactions that pose a threat to life and health of the patient. The effect caused by adverse drug reactions on cardiovascular system is one of the most significant manifestations of drug–drug interaction. Clinical assessment of adverse drug reactions resulting from drug–drug interaction between all drug pairs used in therapeutic practice is not possible. The purpose of this work was to build models using structure–activity analysis to predict adverse effects of drugs on cardiovascular system, mediated by pairwise interactions between the drug pairs when they are taken together. Data on the adverse effects resulting from drug–drug interaction were obtained from the DrugBank database. The data on drug pairs that do not cause such effects, which are necessary for building accurate structure–activity models, were obtained from the TwoSides database, which contains the results of analysis of the spontaneous reports. Two types of descriptors were used to describe a pair of drug structures: PoSMNA descriptors and probabilistic estimates of the prediction of biological activities obtained using the PASS program. Structure–activity relationships were established using the Random Forest method. Prediction accuracy was calculated by means of five-fold cross-validation. The highest accuracy values were obtained using PASS probabilistic estimates as descriptors. The area under the ROC curve was 0.94 for bradycardia, 0.96 for tachycardia, 0.90 for arrhythmia, 0.90 for ECG QT prolongation, 0.91 for hypertension, 0.89 for hypotension.

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KEY WORDS: drug–drug interaction, (Q)SAR, adverse drug reactions

DOI: 10.1134/S0006297923050061

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