ProtPocket is an advanced computational biology pipeline explicitly engineered to discover, analyze, and target undrugged protein complexes. Operating at the intersection of structural informatics and rational drug design, ProtPocket leverages the AlphaFold Protein Structure Database to find cryptic, high-value binding sites that only emerge during protein-protein interactions (PPIs).
By automating geometric cavity detection (fpocket), virtual screening, and molecular docking (AutoDock Vina), ProtPocket accelerates the hit-to-lead workflow for some of the world's most neglected pathogens and hardest-to-treat human diseases.
The core innovation of ProtPocket lies in its structural gap scoring mechanism, which we term the Disorder Delta.
Many critical proteins, especially transcription factors and viral entry proteins, contain Intrinsically Disordered Regions (IDRs). As singular monomers, these regions are highly flexible and lack a defined 3D structure, rendering them effectively "undruggable" by traditional small molecules.
However, upon binding to an interaction partner (forming a homodimer or heterodimer), these disordered regions often undergo a structural phase transition, folding into highly stable confirmations.
ProtPocket exploits this behavior:
- Monomer Confidence (pLDDT): We evaluate the AlphaFold pLDDT (Predicted Local Distance Difference Test) of the monomer. Low pLDDT (<50) indicates high intrinsic disorder.
- Complex Confidence (pLDDT): We evaluate the pLDDT of the same sequence within the predicted homodimeric complex. A dramatic rise in pLDDT (>80) highlights a region forced into stability by the interaction.
- The Delta (Δ): The difference between these two scores (
Δ = Complex pLDDT - Monomer pLDDT) flags the theoretical interface. - Targeting the Interface: By directing geometric cavity detection algorithms precisely at regions with a high Disorder Delta, we identify cryptic pockets that exist only in the functional complex state. Inhibiting these pockets theoretically prevents the protein-protein interaction from occurring at all.
This targeted approach zeroes in on the most vulnerable, mechanistically critical regions of a pathogen's structural machinery.
The platform operates autonomously through a 5-step pipeline:
We ingest and sift through the 1.7 million structures in the AlphaFold Complex Database. We aggressively cross-reference this structural data against the ChEMBL pharmacological database and the World Health Organization (WHO) Priority Pathogens list. Any target with 0 known approved drugs that belongs to a high-threat pathogen (e.g., M. tuberculosis, A. baumannii) or aggressive human disease (e.g., TP53, MYC) is elevated to the dashboard.
The pipeline calculates the thermodynamic Disorder Delta for all filtered targets. Proteins showcasing a massive phase transition from chaotic monomer to stable dimer are ranked at the top of the Undrugged Target Leaderboard.
Using fpocket, a Voronoi tessellation-based cavity detection algorithm, we scan the surface of the newly stabilized complex. We filter the results to isolate alpha-spheres that lie directly on the complex interface, ignoring irrelevant surface clefts.
Finally, we perform high-throughput molecular docking of candidate compounds directly inside the identified pocket using AutoDock Vina. Promising binding affinities (kcal/mol) signify a high-confidence starting point for medicinal chemists.
ProtPocket is built as a highly concurrent monorepo designed for speed and real-time visualization.
- Designed with Go's
goroutinesto allow heavily parallelized live querying of the AlphaFold REST API, UniProt API, and ChEMBL API. - Implements an intelligent, thread-safe memory Cache (
sync.RWMutex) to prevent rate-limiting while serving the high-traffic Undrugged Target Leaderboard. - Framework:
gofr.dev/pkg/gofr - Scoring Engine: Custom Go algorithms implementing the Disorder Gap Delta mathematical models.
- A dark-mode, futuristic UI inspired by modern biotech, utilizing Vanilla Tailwind CSS for lightning-fast performance without heavy component libraries.
- React Router DOM for instantaneous page transitions.
- We embed Mol*, an ultra-fast WebGL macromolecular viewer capable of streaming
.ciftrajectory data directly from AlphaFold servers. - Custom Implementations:
- Live side-by-side comparative views of Monomeric vs. Complex topologies.
- On-the-fly pLDDT confidence coloring (
blue= rigid interface,red= disordered chaos). - Multi-pose trajectory viewing for AutoDock Vina binding conformation results.
The backend engine serves the API endpoints (e.g., /search, /complex, /undrugged).
cd ProtPocket
go mod download
go run main.go
# The server will start on http://localhost:8000The Vite dev server provides hot-module reloading for the UI.
cd ProtPocket/app
npm install
npm run dev
# The UI will load on http://localhost:5173ProtPocket is proudly open-source and built for the global structural biology community.
This platform relies on the shoulders of giants. We heavily utilize data and tools from the following projects:
- AlphaFold Protein Structure Database: DeepMind, EMBL-EBI. Website
- UniProt: The Universal Protein Resource. Website
- ChEMBL: EMBL-EBI database of bioactive molecules with drug-like properties. Website
- fpocket: Open source protein cavity detection. GitHub
- AutoDock Vina: Fast, accurate open-source molecular docking. GitHub
- Mol*: A comprehensive web-based macromolecular visualization toolkit. Website
"The shapes of proteins are the locks of biology; we are searching for the keys."