Systematic exploration of synergistic drug pairs

Molecular Systems Biology

Murat Cokol⁵  Hon Nian Chua⁵  Murat Tasan⁵  Beste Mutlu⁴  Zohar B Weinstein⁴  Yo Suzuki⁵  Mehmet E Nergiz¹  Michael Costanzo³  Anastasia Baryshnikova³  Guri Giaever³  Corey Nislow³  Chad L Myers²  Brenda J Andrews³  Charles Boone³ 

[1] Department of Computer Engineering, Faculty of Engineering, Zirve University, Gaziantep, Turkey;Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, MN, USA;Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada;Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey;Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

关键词: chemical genetics;    drug combinations;    drug discovery;    genetic interactions;   

DOI  :  10.1038/msb.2011.71

来源: Wiley

【 摘 要 】

Abstract

Drug synergy allows a therapeutic effect to be achieved with lower doses of component drugs. Drug synergy can result when drugs target the products of genes that act in parallel pathways (‘specific synergy’). Such cases of drug synergy should tend to correspond to synergistic genetic interaction between the corresponding target genes. Alternatively, ‘promiscuous synergy’ can arise when one drug non-specifically increases the effects of many other drugs, for example, by increased bioavailability. To assess the relative abundance of these drug synergy types, we examined 200 pairs of antifungal drugs in S. cerevisiae. We found 38 antifungal synergies, 37 of which were novel. While 14 cases of drug synergy corresponded to genetic interaction, 92% of the synergies we discovered involved only six frequently synergistic drugs. Although promiscuity of four drugs can be explained under the bioavailability model, the promiscuity of Tacrolimus and Pentamidine was completely unexpected. While many drug synergies correspond to genetic interactions, the majority of drug synergies appear to result from non-specific promiscuous synergy.

Synopsis

Two types of drug synergy, genetic and promiscuous, are explored in S. cerevisiae. The results suggest that promiscuous synergy predominates, and that propensity to synergize is an intrinsic drug property with the potential to accelerate the search for synergistic drug combinations.

• Discovered 37 synergistic interactions among antifungal chemicals
• Promiscuous synergy is the predominant form of drug synergy
• Rate of synergy is an intrinsic property of drugs that can guide searches for drug synergy

【 授权许可】

CC BY-NC-SA   
Copyright © 2011 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.