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Small Glycols Discover Cryptic Pockets on Proteins for Fragment-Based Approaches

Bansia, H and Mahanta, P and Yennawar, NH and Ramakumar, S (2021) Small Glycols Discover Cryptic Pockets on Proteins for Fragment-Based Approaches. In: Journal of Chemical Information and Modeling .

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Official URL: https://doi.org/10.1021/acs.jcim.0c01126


Cryptic pockets are visible in ligand-bound protein structures but are occluded in unbound structures. Utilizing these pockets in fragment-based drug-design provides an attractive option for proteins not tractable by classical binding sites. However, owing to their hidden nature, they are difficult to identify. Here, we show that small glycols find cryptic pockets on a diverse set of proteins. Initial crystallography experiments serendipitously revealed the ability of ethylene glycol, a small glycol, to identify a cryptic pocket on the W6A mutant of the RBSX protein (RBSX-W6A). Explicit-solvent molecular dynamics (MD) simulations of RBSX-W6A with the exposed state of the cryptic pocket (ethylene glycol removed) revealed closure of the pocket reiterating that the exposed state of cryptic pockets in general are unstable in the absence of ligands. Also, no change in the pocket was observed for simulations of RBSX-W6A with the occluded state of the cryptic pocket, suggesting that water molecules are not able to open the cryptic pocket. "Cryptic-pocket finding"potential of small glycols was then supported and generalized through additional crystallography experiments, explicit-cosolvent MD simulations, and protein data set construction and analysis. The cryptic pocket on RBSX-W6A was found again upon repeating the crystallography experiments with another small glycol, propylene glycol. Use of ethylene glycol as a probe molecule in cosolvent MD simulations led to the enhanced sampling of the exposed state of experimentally observed cryptic sites on a test set of two proteins (Niemann-Pick C2, Interleukin-2). Further, analyses of protein structures with validated cryptic sites showed that ethylene glycol molecules bind to sites on proteins (Bcl-xL, G-actin, myosin II, and glutamate receptor 2), which become apparent upon binding of biologically relevant ligands. Our study thus suggests potential application of the small glycols in experimental and computational fragment-based approaches to identify cryptic pockets in apparently undruggable and/or difficult targets, making these proteins amenable to drug-design strategies. © 2020 American Chemical Society. All rights reserved.

Item Type: Journal Article
Publication: Journal of Chemical Information and Modeling
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to American Chemical Society
Keywords: Aliphatic compounds; Binding sites; Crystallography; Ethylene; Ethylene glycol; Ligands; Molecular dynamics; Molecules; Organic solvents; Polyols, Drug design strategies; Enhanced samplings; Explicit solvent molecular dynamics; Glutamate receptor; Probe molecules; Propylene glycols; Protein structures; Water molecule, Proteins
Department/Centre: Division of Physical & Mathematical Sciences > Physics
Date Deposited: 17 Mar 2021 10:30
Last Modified: 17 Mar 2021 10:30
URI: http://eprints.iisc.ac.in/id/eprint/68405

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