BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1506220000?filename=MODEL1506220000_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1506220000?filename=MODEL1506220000_urn.xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1506220000?filename=MODEL1506220000.vcmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1506220000?filename=MODEL1506220000.scihttps://www.ebi.ac.uk/biomodels/model/download/MODEL1506220000?filename=MODEL1506220000.pngprimaryOK200Steven WattersonNon-curatedordinary differential equation modelL2V4https://www.ebi.ac.uk/biomodels/MODEL150622000028910500falseBioModelsSBMLModelsBenson2017 Systems Pharmacology Multidrug (cholesterol biosynthesis pathway)2017MODEL1506220000Helen E Benson, Steven Watterson, Joanna L Sharman, Chido P Mpamhanga, Andrew Parton, Christopher Southan, Anthony J Harmar, Peter GhazalHelen E Benson28910500, <h4>Background and purpose</h4>An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway.<h4>Experimental approach</h4>Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment.<h4>Key results</h4>We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi-drug treatments with high efficacy and minimal off-target effects.<h4>Conclusion and implications</h4>We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses.. 23, 174. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.s.watterson@ulster.ac.ukUniversity of Ulster<h4>Background and purpose</h4>An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway.<h4>Experimental approach</h4>Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment.<h4>Key results</h4>We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi-drug treatments with high efficacy and minimal off-target effects.<h4>Conclusion and implications</h4>We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses.Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway.Benson Helen E HE, Watterson Steven S, Sharman Joanna L JL, Mpamhanga Chido P CP, Parton Andrew A, Southan Christopher C, Harmar Anthony J AJ, Ghazal Peter Pimprinted and ancient gene protein, treatment, Therapy, study, mode of action, cholesterol synthesis, pharmacodynamics, postnatal development, cholesterol anabolism., postnatal growth, cholesterol formation, growth and development, Ximpact, Treatments, impact-a, development, pharmacologic action, mechanism of action, Therapeutic, disease management, Therapies, IMPACT, imprinted and ancient gene protein homolog, Treatment, cholesterol biosynthesis, Pharmacologies, E430016J11Rik, growth, RWDD5extent, mode of action, IPP2A2, pharmacodynamics, Public Sectors, PLXN5, Product, determination, postnatal development, Nl1, growth and development, side effects, SeP, limitations, 5730420M11Rik, Readability, Personal, CEH, Anniversary, Pharmaceutical Product, 17alpha)-cholest-5-en-3-ol, NEPII, NL1, 3, NL2, SEH, Public Enterprise, study limitations, 14beta, medicament, SEP, Sep, imprinted and ancient gene protein, Psychological, treatment, SET, (3beta, Biology, TAF-I, Public Domains, Cholest-5-en-3beta-ol, racemic mevalonate, Epicholesterol, sEP, DmelCG4299, Social, IGAAD, set, DmelCG10574, Dedications, medicine, Pharmaceutical, cholesterol anabolism, disease management, Therapies, Social Power, Event, Reference Standard, Power, Therapy, close to, phapii, Standard Preparation, Standard Preparations, Standardization, Data Set, completeness, acid, incomplete, StF-IT-1, Psychological Powers, Pentanoic acid, abolished, Special Events, MMEL2, Public Domain, Domains, Pharmaceutic, Nucl, Domain, Acid, Special Event, HLA-DR-associated protein II, DI-2, Standard, 5-dihydroxy-3-methyl-, acide, I-2Dm, acids, CG4299, acido, Treatments, RS-mevalonate, experimental procedures, I-2PP1, Sector, TAF-IBETA, pharmaceuticals, Eph2, TAF-Ibeta, rac-mevalonate, E430016J11Rik, Powers, i2pp2a, D0Nds28, Psychological Power, B530004O11Rik, Sectors, criteria, (+-)-mevalonate, experimental, Professional Power, PLEXIN-B1, Mevalonic, Copyrights, Special, guidelines, Ximpact, PHAPII, D1Nds28, Cholest-5-en-3-ol (3beta)-, (RS)-mevalonate, farmaco, Mevalonate, Enterprises, Drugs, mevalonic acid anion, study, CG2916, cholesterol synthesis, methods, lateral shoot, experimental section, ipp2a2, cholesterol formation, 2pp2a, Events, Public Enterprises, CG10574, Solution, drugs, Abstract, Reference, 2PP2A, mechanism of action, taf-ibeta, SELP, dSET, dSet, Preparation, Pharmacologies, Enterprise, Saeure, axillary shoot, Pharmaceuticals, Products, drug, igaad, Mell1, Medications, impact-a, group, near to, Anniversaries, development, sep5, I-2PP2A, Public, Systems, chemical analysis, Dm I-2, I2PP2A, IMPACT, imprinted and ancient gene protein homolog, Professional, cholesterol biosynthesis, Cholesterin, Data Base, C23, Pharmaceutic Preparations, ensemble, Saeuren, postnatal growth, DmelCG2916, Understanding, Drug, dSET/TAF-Ibeta, Preparations, Personal Power, 2610030F17Rik, pharmacologic action, Therapeutic, approaches, vicinity of, Standards, Power (Psychology), Treatment, Public., assay, Pharmaceutical Products, AA407739, growth, RWDD5, NEP2, Pharmaceutical Preparationcholesterol formation, mode of action, cholesterol synthesis, cholesterol biosynthesis, pharmacodynamics, pharmacologic action, mechanism of action, Pharmacologies, cholesterol anabolism.mode of action, IPP2A2, pharmacodynamics, Product, determination, Combination, sci, side effects, limitations, 5730420M11Rik, Readability, Personal, Pharmaceutical Product, HOW, How, 17alpha)-cholest-5-en-3-ol, 3, Drug Combination, study limitations, Work Flow, 14beta, medicament, l(3)j5D5, IKKg, KEY, Key, 24B, imprinted and ancient gene protein, Psychological, treatment, SET, (3beta, Biology, TAF-I, stru, Cholest-5-en-3beta-ol, Futurology, l(3)S053606, CG10293, racemic mevalonate, Epicholesterol, DmelCG4299, Social, l(3)j5B5, IGAAD, set, DmelCG10574, medicine, Pharmaceutical, cholesterol anabolism, disease management, Therapies, Social Power, Reference Standard, Power, Predictions and Projections, close to, phapii, Therapy, Standard Preparation, 0904/17, Standard Preparations, Standardization, Data Set, incomplete, StF-IT-1, Psychological Powers, results, Pentanoic acid, abolished, DmIKKgamma, Workflows, SZ1, dIKK, Kenny, Pharmaceutic, Acid, HLA-DR-associated protein II, DI-2, Standard, 5-dihydroxy-3-methyl-, I-2Dm, IKK-gamma, CG4299, Treatments, RS-mevalonate, I-2PP1, Health, TAF-IBETA, DmelCG16910, antagonists and inhibitors, pharmaceuticals, anon-EST:Liang-2.39, TAF-Ibeta, rac-mevalonate, E430016J11Rik, Powers, i2pp2a, Work Flows, Psychological Power, criteria, (+-)-mevalonate, Health Resource, Professional Power, P62, Mevalonic, guidelines, Ximpact, dIKK-gamma, PHAPII, Combinations, Cholest-5-en-3-ol (3beta)-, (RS)-mevalonate, farmaco, DmIKK-gamma, Mevalonate, Projections and Predictions, dmIKKgamma, IKK[[gamma]], Resources, Drugs, mevalonic acid anion, cholesterol synthesis, l(3)s2612, lateral shoot, ipp2a2, cholesterol formation, inhibiteur, 2pp2a, CG10574, Solution, drugs, Reference, 2PP2A, inhibidor, mechanism of action, IKK, taf-ibeta, DmelCG10293, dSET, dSet, Preparation, Pharmacologies, axillary shoot, Pharmaceuticals, inhibitors, Products, clone 2.39, drug, igaad, inhibitor, Medications, qkr, l(3)S090417, impact-a, group, near to, IKKgamma, disease management., Resource, I-2PP2A, KH93F, Systems, chemical analysis, Dm I-2, I2PP2A, IMPACT, imprinted and ancient gene protein homolog, Professional, cholesterol biosynthesis, background, Cholesterin, who, antagonists, Pharmaceutic Preparations, ensemble, Dmikkgamma, Who/How, Understanding, CG16910, introduction, Drug, dSET/TAF-Ibeta, Preparations, Personal Power, 2610030F17Rik, pharmacologic action, Therapeutic, approaches, vicinity of, Standards, Power (Psychology), qkr[93F], Treatment, assay, Pharmaceutical Products, AA407739, Future, RWDD5, Pharmaceutical PreparationfalseBenson2017 - Systems Pharmacology Multidrug (cholesterol biosynthesis pathway) BensonWattersonetal_SystemsPharmacology_Multidrug This model is described in the article: Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway. Benson H, Watterson S, Sharman J, Mpamhanga C, Parton A, Southan C, Harmar A, Ghazal P. Br. J. Pharmacol. 2017 Sep; : Abstract: An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway.Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimisation to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment.We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi-drug treatments with high efficacy and minimal off-target effects.We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology work-flow for the refinement of data and the generation of future therapeutic hypotheses. This model is hosted on BioModels Database and identified by: MODEL1506220000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. 2017-09-262017-09-262015-06-22MODEL150622000028910500MODEL1506220000