Target-independent prediction of drug synergies using only drug lipophilicity

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Yılancıoğlu, Kaan and Weinstein, Zohar Bat-El and Meydan, Cem and Akhmetov, Azat and Toprak, Işıl and Durmaz, Arda and Iossifov, Ivan and Kazan, Hilal and Roth, Frederick P. and Çokol, Murat (2014) Target-independent prediction of drug synergies using only drug lipophilicity. Journal of Chemical Information and Modeling, 54 (8). pp. 2286-2293. ISSN 1549-9596 (Print) 1549-960X (Online)

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Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds ("drugs") previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms.
Item Type: Article
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Engineering and Natural Sciences > Academic programs > Biological Sciences & Bio Eng.
Faculty of Engineering and Natural Sciences > Basic Sciences > Chemistry
Faculty of Engineering and Natural Sciences > Academic programs > Computer Science & Eng.
Faculty of Engineering and Natural Sciences
Depositing User: Murat Çokol
Date Deposited: 23 Nov 2014 22:44
Last Modified: 02 Aug 2019 10:31

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