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Figure 1

From: Connecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington’s Disease Model through the Application of Quantitative Systems Pharmacology

Figure 1The alternative text for this image may have been generated using AI.

Chemogenomics component of the QSP platform. (a) Libraries of mechanism annotated probe compounds are screened in a clinically relevant phenotypic assay to identify phenotype modulating probes. (b) Targets for the active probes are identified from various drug-target databases and then are associated with biological pathways using information from protein-pathway databases. (c) Using a systems level analysis of all pathways identified, computational analysis is performed to predict the optimal modulating pathways/networks based on the activity of the respective probes (i.e., activation or inhibition of pathways in relation to the known effects of the pathway on the phenotype). (d) Predicted pathway/network hypotheses are tested in phenotypic assays by i) testing additional compounds known to modulate the pathways, ii) testing compounds predicted by advanced machine learning methods that will modulated the pathway, iii) modulate pathways by knock-down and knock-in approaches, and/or iv) evaluate probes in pathway specific phenotypic assays. If pathways are not confirmed, then the hypothesis is refined with the new information gained from the testing, additional probes are identified, and the new hypothesis is tested. If pathways are confirmed, then the active probes are advanced to in vivo testing. (e) At the initial screening analysis stage, the heterogeneity of phenotype modulating response is assessed. If no heterogeneity is detected, then proceed as above. However, if heterogeneity is detected, then hypotheses are developed and tested to characterize the basis of the heterogeneity (e.g., effects of combinations of different compounds). The information gained from the heterogeneity analysis is used to inform the prediction of the phenotype modulating pathways/networks. (f) The outputs of this strategy are i) a systems level understanding of the pathways/networks involved in the clinically relevant phenotype which enables the design of optimal therapeutic strategies, and ii) probes/drugs that can be advanced to in vivo and clinical testing.

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