Comprehensive detection and characterization of human druggable pockets through binding site descriptors

Arnau Comajuncosa-Creus, Guillem Jorba, Xavier Barril and Patrick Aloy ()
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Arnau Comajuncosa-Creus: The Barcelona Institute of Science and Technology
Guillem Jorba: The Barcelona Institute of Science and Technology
Xavier Barril: Universitat de Barcelona
Patrick Aloy: The Barcelona Institute of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Druggable pockets are protein regions that have the ability to bind organic small molecules, and their characterization is essential in target-based drug discovery. However, deriving pocket descriptors is challenging and existing strategies are often limited in applicability. We introduce PocketVec, an approach to generate pocket descriptors via inverse virtual screening of lead-like molecules. PocketVec performs comparably to leading methodologies while addressing key limitations. Additionally, we systematically search for druggable pockets in the human proteome, using experimentally determined structures and AlphaFold2 models, identifying over 32,000 binding sites across 20,000 protein domains. We then generate PocketVec descriptors for each site and conduct an extensive similarity search, exploring over 1.2 billion pairwise comparisons. Our results reveal druggable pocket similarities not detected by structure- or sequence-based methods, uncovering clusters of similar pockets in proteins lacking crystallized inhibitors and opening the door to strategies for prioritizing chemical probe development to explore the druggable space.

Date: 2024
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DOI: 10.1038/s41467-024-52146-3

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