From single drug targets to synergistic network pharmacology in ischemic stroke
| Autor: | Emre Guney, Mahmoud H. Elbatreek, Harald H.H.W. Schmidt, Jan Baumbach, Javier Egea, Simon J. Larsen, Vanessa Gómez-Rangel, Ana I. Casas, Pamela W. M. Kleikers, Manuela G. López, Ahmed A. Hassan |
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| Přispěvatelé: | Pharmacology and Personalised Medicine, RS: FHML non-thematic output |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male PREDICTION Pyrazoles/pharmacology Nitric Oxide Synthase Type II Disease Nitric Oxide Synthase Type I OXYGEN Brain Ischemia Mice 0302 clinical medicine Cell Death/drug effects Drug Discovery Nitric Oxide Synthase Type II/genetics Nitric Oxide Synthase/drug effects BRAIN Stroke network analysis media_common Multidisciplinary NADPH oxidase biology Cell Death Drug discovery NOX4 Drug Synergism Biological Sciences stroke ddc 3. Good health Drug Combinations NG-Nitroarginine Methyl Ester PNAS Plus Blood-Brain Barrier NADPH Oxidase 4 SIMILARITY Nitric Oxide Synthase Type III/genetics Network analysis Female Stroke/drug therapy Blood-Brain Barrier/metabolism Drug EXPRESSION Nitric Oxide Synthase Type III Pyridones media_common.quotation_subject NOS1 BIOLOGY 03 medical and health sciences HYDROGEN-PEROXIDE In vivo Reactive Oxygen Species/metabolism medicine network pharmacology Animals NG-Nitroarginine Methyl Ester/pharmacology Pyridones/pharmacology Pharmacology NITRIC-OXIDE business.industry NADPH Oxidase 4/drug effects Brain Ischemia/drug therapy medicine.disease OFF-TARGET Disease Models Animal 030104 developmental biology CELLS biology.protein Pyrazoles Nitric Oxide Synthase Type I/genetics Nitric Oxide Synthase business Reactive Oxygen Species Neuroscience 030217 neurology & neurosurgery Network pharmacology |
| Zdroj: | Casas, A I, Hassan, A A, Larsen, S J, Gomez-Rangel, V, Elbatreek, M, Kleikers, P W M, Guney, E, Egea, J, López, M G, Baumbach, J & Schmidt, H H H W 2019, ' From single drug targets to synergistic network pharmacology in ischemic stroke ', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 14, pp. 7129-7136 . https://doi.org/10.1073/pnas.1820799116 Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 116(14), 7129-7136. National Academy of Sciences Proceedings of the National Academy of Sciences |
| ISSN: | 0027-8424 |
| DOI: | 10.1073/pnas.1820799116 |
| Popis: | Significance Current one drug–one target–one disease approaches in drug discovery have become increasingly inefficient. Network pharmacology defines disease mechanisms as networks best targeted by multiple, synergistic drugs. Using the high unmet medical need indication stroke, we here develop an integrative in silico approach based on a primary target, NADPH oxidase type 4, to identify a mechanistically related cotarget, NO synthase, for network pharmacology. Indeed, we validate both in vivo and in vitro, including humans, that both NOX4 and NOS inhibition is highly synergistic, leading to a significant reduction of infarct volume, direct neuroprotection, and blood–brain-barrier stabilization. This systems medicine approach provides a ground plan to decrease current failure in the field by being implemented in other complex indications. Drug discovery faces an efficacy crisis to which ineffective mainly single-target and symptom-based rather than mechanistic approaches have contributed. We here explore a mechanism-based disease definition for network pharmacology. Beginning with a primary causal target, we extend this to a second using guilt-by-association analysis. We then validate our prediction and explore synergy using both cellular in vitro and mouse in vivo models. As a disease model we chose ischemic stroke, one of the highest unmet medical need indications in medicine, and reactive oxygen species forming NADPH oxidase type 4 (Nox4) as a primary causal therapeutic target. For network analysis, we use classical protein–protein interactions but also metabolite-dependent interactions. Based on this protein–metabolite network, we conduct a gene ontology-based semantic similarity ranking to find suitable synergistic cotargets for network pharmacology. We identify the nitric oxide synthase (Nos1 to 3) gene family as the closest target to Nox4. Indeed, when combining a NOS and a NOX inhibitor at subthreshold concentrations, we observe pharmacological synergy as evidenced by reduced cell death, reduced infarct size, stabilized blood–brain barrier, reduced reoxygenation-induced leakage, and preserved neuromotor function, all in a supraadditive manner. Thus, protein–metabolite network analysis, for example guilt by association, can predict and pair synergistic mechanistic disease targets for systems medicine-driven network pharmacology. Such approaches may in the future reduce the risk of failure in single-target and symptom-based drug discovery and therapy. |
| Databáze: | OpenAIRE |
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