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SURFMAP: Unbiased Ligand Binding Simulations for Cryptic Allosteric Site Discovery
Overview
Allostery plays a primary role in regulating protein activity, making it a critical mechanism in human disease and drug discovery. However, identifying allosteric regulatory sites remains a major challenge because they are often "cryptic" and lack clear geometric or chemical features.
SURFMAP provides a generalizable computational protocol to predict these hidden allosteric ligand binding sites based on unbiased ligand binding simulation trajectories. By mapping the dynamic paths of small molecules, SURFMAP uncovers transient, intermediate binding pockets that are typically unobservable in static X-ray crystal structures.
Key Features & Scientific Validation
Generalizable Computational Workflow: Combines long-timescale unbiased molecular dynamics (MD) simulations, virtual screening, and experimental testing to reveal targetable allosteric sites on dynamic proteins.
Proven Model Success (Src Kinase): Successfully re-evaluated ligand binding pathways for the proto-oncogene Src kinase, identifying three intermediate states: two known allosteric sites (PIF and MYR pockets) and one novel pocket termed the G-loop site.
High-Throughput Virtual Screening: Enables virtual docking screens (e.g., using DOCK6.6 against extensive compound databases like the ZINC library) to score, rank, and identify high-affinity binders based on Cartesian energy scores and footprint-based similarity.
Discovery of Specific Allosteric Inhibitors: Validated by identifying Compound 1C, a V-type non-competitive inhibitor that targets the Src G-loop site with high selectivity over closely related kinases like Hck and Abl.
Conformation-Selective Targeting: Biophysically proven to selectively target and stabilize active protein conformations, offering a robust strategy for designing next-generation allosteric modulators and targeted degraders (PROTACs).
What is Tamarind Bio?
Tamarind Bio is an advanced structure-based drug discovery and computational platform that hosts state-of-the-art tools like SURFMAP. By leveraging massive structural biology libraries and computational docking software (such as DOCK6.6, MOE, and fpocket analytics), Tamarind Bio transitions static structural snapshots into dynamic, ensemble-based drug design pipelines. The platform empowers researchers to bypass the limitations of highly conserved orthosteric binding sites, enabling the discovery of highly specific allosteric ligands that mitigate off-target toxicity and drug resistance.
How to Use SURFMAP on Tamarind Bio
Follow this validated computational workflow to discover novel allosteric binding pockets on your target protein:
Input Trajectory Generation & Selection: Upload your long-timescale unbiased ligand binding molecular dynamics (MD) simulation trajectories. Extract a representative, stable snapshot configuration of your target protein where a transient intermediate pocket is revealed.
Pocket Evaluation: Run the automated pocket detection suite (utilizing fpocket parameters) to evaluate the physicochemical characteristics, volume, and druggability score of the newly exposed cryptic site.
Target Preparation: Automatically add hydrogen atoms and force field charges (using parameters like ff99sb) to prepare the clean, solvent-removed protein kinase domain structure for flexible docking.
Virtual Screen Execution: Filter and select your ligand libraries from integrated databases (e.g., ZINC subset filtration based on custom charge, rotatable bonds, and molecular weight parameters). Launch the automated DOCK sequence.
Multi-Metric Rescoring & Selection: Filter your raw docking outputs using SURFMAP's integrated scoring criteria:
DOCK Cartesian Energy (DCEsum): Quantify the sum of Van der Waals and electrostatic energies.
Ligand Efficiency (Ligeff): Identify smaller molecular weights acting as efficient starting chemical scaffolds.
Footprint Descriptor Scoring (FPSsum): Evaluate binding mode and pose similarity against a reference binder to maximize selection diversity.
Download Candidates: Extract the highest-ranking diversified cluster heads for immediate experimental, biochemical, and biophysical validation assays (such as continuous coupled-kinase assays or STD-NMR profiling).