Use Case — Peer-Reviewed

AI-Powered Target Identification & Deconvolution

In a peer-reviewed study, Plex's AI platform identified novel drug targets from phenotypic screening data — predictions that were then validated in biochemical assays and a mouse model of liver disease, reducing hepatic steatosis by 68%.

Phenotypic Screening Coupled with AI-Driven Target Deconvolution Identifies α-Terthienyl as a Dual DPP-IV/HSD17β13 Modulator with Efficacy in a Mouse Model of MASLD

Hoegeman KM, Wotring JW, Fursmidt R, Gaetz J, Khalil EM, Selinger DW, Schultz TL, McCarty SM, O'Meara MJ, Clasby MC, Sexton JZ · bioRxiv (2025) · University of Michigan & Plex Research Inc.

Read the paper →
Get a Free Report Based on Your Science

The Challenge: Target Deconvolution in Phenotypic Drug Discovery

Phenotypic screening identifies compounds that work in disease-relevant cell models — but it doesn't tell you why they work. Target deconvolution (identifying the molecular targets of a hit compound) traditionally requires months of pull-down assays, affinity chromatography, and genetic knockdown experiments. This bottleneck delays the transition from hit to lead and limits the ability to optimize compounds rationally.

How Plex Solved It

Chain of evidence showing how Plex linked α-terthienyl to DPP-IV and HSD17β1 through similarity analysis and binding database predictions
Figure 4 from Hoegeman et al. (2025). Chain of evidence showing selected targets linking α-terthienyl to DPP-IV and HSD17β1 via structural similarity analysis and binding database cross-referencing.

Researchers at the University of Michigan used Plex's AI platform for target deconvolution of their lead compound, α-terthienyl, identified from a high-content phenotypic screen for MASLD (fatty liver disease). Plex integrated the compound's chemical structure, quantitative phenotypic fingerprint, and biological knowledge graphs from 60+ public databases to generate focal graphs — knowledge subgraphs analyzed using centrality algorithms like PageRank — that ranked protein target hypotheses by probability.

What Plex Identified

  • DPP-IV (dipeptidyl peptidase 4) — a validated metabolic target, confirmed by biochemical assay with IC50 of 1.47 μM
  • HSD17β13 (17-beta hydroxysteroid dehydrogenase 13) — a genetically validated MASLD target, confirmed by enzymatic inhibition assay
  • Dual-target polypharmacology — Plex predicted the compound would act through both targets simultaneously, a mechanism validated in vivo
  • 8 total target hypotheses ranked by confidence, with the top predictions confirmed experimentally

Validated Results

The Plex-predicted targets were validated across multiple experimental approaches: molecular docking confirmed binding affinity, biochemical assays confirmed enzymatic inhibition, and an in vivo mouse model demonstrated 68% reduction in hepatic steatosis, near-complete resolution of microvesicular steatosis, significantly improved glucose tolerance, and normalized liver biomarkers (ALT/AST). The compound showed an EC50 of 106 nM with no cytotoxicity up to 15 μM.

H&E-stained liver sections comparing vehicle control, healthy control, and α-terthienyl treated mice, with glucose tolerance and liver weight data
Figure 3 from Hoegeman et al. (2025). H&E-stained liver sections of (A) vehicle control, (B) healthy control, and (C) α-terthienyl treated mice at 5 mg/kg showing resolution of steatosis. (D) Improved glucose tolerance and decreased liver weight in treated animals.

Key Capabilities Demonstrated

  • AI-driven target deconvolution from phenotypic screening data — no prior target hypothesis required
  • Multi-modal integration of chemical structures, phenotypic fingerprints, and biological knowledge graphs
  • Focal Graph analysis using PageRank-style algorithms to rank target hypotheses by probability
  • Rapid identification of polypharmacological mechanisms that would take months to discover experimentally
  • Predictions validated by independent biochemical assays and in vivo disease models
Biochemical inhibition of DPP-IV, HSD17β13 activity assay, and molecular docking of α-terthienyl into DPP-IV and HSD17β13 binding pockets
Figure 5 from Hoegeman et al. (2025). (A) Biochemical inhibition of DPP-IV. (B) In cellulo activity of HSD17β13. (C–D) Molecular docking of α-terthienyl into DPP-IV and HSD17β13 binding pockets confirming predicted binding interactions.

See What Plex Can Identify in Your Therapeutic Area

Get a free report based on your science. Our AI will analyze your pipeline and surface novel target opportunities — the same platform validated in peer-reviewed research.

Get a Free Report Based on Your Science