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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations.

Gerard Martinez-Rosell¹, Silvia Lovera², Zara A Sands²

¹Acellera Labs, C/Doctor Trueta 183, 08005 Barcelona, Spain.

Journal of Chemical Information and Modeling

|March 17, 2020

Summary

This study introduces CrypticScout, a new computational method using molecular dynamics (MD) simulations with benzene probes to discover hidden protein pockets. This advances structure-based drug discovery by expanding the druggable proteome.

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Area of Science:

Computational chemistry
Structural biology
Drug discovery

Background:

Cryptic pockets are protein cavities often hidden in apo structures, requiring ligands for visualization.
Identifying cryptic pockets is vital for structure-based drug discovery to target new protein modulations.
Expanding the druggable space is a key challenge in developing novel therapeutics.

Purpose of the Study:

To present a novel computational method for detecting cryptic pockets in proteins.
To introduce a web application, CrypticScout, for accessible cryptic pocket identification.
To validate the method's efficacy across diverse protein systems.

Main Methods:

Utilizing mixed-solvent molecular dynamics (MD) simulations with benzene as a hydrophobic probe.
Employing an all-atom MD-based workflow for comprehensive pocket detection.
Systematic validation on 18 different protein systems and 5 additional kinases.

Main Results:

CrypticScout successfully identifies benzene probe binding hotspots on protein surfaces.
The method maps probe occupancy, residence time, and residence time-weighted occupancy.
Demonstrated robustness through extensive testing on multiple protein targets.

Conclusions:

The developed method and web application provide a powerful tool for discovering cryptic pockets.
This approach enhances the potential for structure-based drug discovery by revealing new binding sites.
CrypticScout facilitates the exploration of previously inaccessible regions of the druggable proteome.