title: Target-independent prediction of drug synergies using only drug lipophilicity.
abstract: 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.
authors.affiliation: Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, ⊥Faculty of Engineering and Natural Sciences, Computer Science and Engineering Program, and ▽Nanotechnology Research and Application Center, Sabanci University , Istanbul 34956, Turkey.
authors.forename: Kaan
authors.initials: K
authors.lastname: Yilancioglu
authors.forename: Zohar B
authors.initials: ZB
authors.lastname: Weinstein
authors.forename: Cem
authors.initials: C
authors.lastname: Meydan
authors.forename: Azat
authors.initials: A
authors.lastname: Akhmetov
authors.forename: Isil
authors.initials: I
authors.lastname: Toprak
authors.forename: Arda
authors.initials: A
authors.lastname: Durmaz
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.forename: Hilal
authors.initials: H
authors.lastname: Kazan
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.forename: Murat
authors.initials: M
authors.lastname: Cokol
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000633:toxicity; D001561:Benzilates / Q000737:chemistry / Q000633:toxicity; D003663:Decision Trees; D004357:Drug Synergism; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015233:Models, Statistical; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009662:Nortropanes / Q000737:chemistry / Q000633:toxicity; D010419:Pentamidine / Q000737:chemistry / Q000494:pharmacology; D000077291:Terbinafine; D014311:Triprolidine / Q000737:chemistry / Q000633:toxicity
chemical_list: D000935:Antifungal Agents; D001549:Benzamides; D001561:Benzilates; D009281:Naphthalenes; D009662:Nortropanes; C003330:trospium chloride; D014311:Triprolidine; D010419:Pentamidine; D000077291:Terbinafine; C100146:trimethobenzamide