Quantitative modeling of dose-response and drug combination based on pathway network
Background: Quantitative description of dose-response of a drug for complex systems is essential fortreatment of diseases and drug discovery.Given the growth of large-scale biological data obtained by multi-levelassays.computational modeling has become an important approach to understand the mechanism of drug action.However,due lo complicated interactions between drugs and cellular targets,the prediction of drug efficacy is a challenge,especially for complex systems.And the biological systems can be regarded as networks,where nodes represent molecular entities(DNA,RNA,protein and small compound)and processes,edges represent the relationships between nodes.Thus we combine biological pathway-based network modeling and molecular docking to evaluate drugefficacy.Rcsults:Network efficiency(NF)and network flux(NF)arc both global measures of the network connectivity.In this work,we used NF and NF to quantitatively evaluate the inhibitory effects of compounds against thelipopolysaccharide-induced productionof prostaglandin E2.The edge values of the pathway network of this biological process were reset according to the Michaclis-Menten equation,which used the binding constant and drug concentration to determine the degree of inhibition of the target protein in the pathway.The combination of NE and NF was adopted to evaluate the inhibitory effects.The dose-response curve was sigmoid and the BC50 values of five compounds were in good agreement with experimental results(R2=0.93).Moreover,we found that two drugsprodnccd maximal synergism when they were combined according to the ratiobetweeneach EC50.Conclusions:Thisquantitative modelhas the ability to predict the dose-response relationships of single drug and drug combination in the context of the pathway network of biological process.These findings are valuable for the evaluation of drug efficacy and thus provide an effective approach for pathway network-based drag discovery.
dosc-rcsponsc modeling drug combination LPS-induccdPGE2 production pathway network
Jiangyong GU Xinzhuang Zhang Yimin Ma Na Li Fang Lno Liang Cao Zhenzhong Wang Gu Yuan Lirong Chen Wei Xiao Xiaojie Xu
Beijing National Laboratory for Molecular Sciences(BNLMS),State Key Laboratory of Rare Earth Materia Beijing National Laboratory for Molecular Sciences(BNLMS),State Key Laboratory of Rare Earth Materia National Key Laboratory of Pharmaceutical New Technology for Chinese Medicine,Kanion Pharmaceutical
国内会议
大连
英文
692-714
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）