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PreprintCited by 12Computational Drug Discovery MethodsProtein Structure and DynamicsEnzyme Structure and Function

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VirtuousPocketome: A Computational Tool for Screening Protein-ligand Complexes to Identify Similar Binding Sites

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Pallante, Lorenzo, Cannariato, Marco, Androutsos, Lampros, Zizzi, Eric A., Bompotas, Agorakis, Hada, Xhesika, Grasso, Gianvito, Kalogeras, Athanasios, Mavroudi, Seferina, di Benedetto, Giacomo, Theofilatos, Konstantinos, Deriu, Marco A.·2023·Scientific Reports
DOI 10.1101/2023.12.12.571207PMC PMC10943019

Preprint — published as 10.1038/s41598-024-56893-7 · Paper page

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Abstract

Protein residues within binding pockets play a critical role in determining the range of ligands that can interact with a protein, influencing its structure and function. Identifying structural similarities in proteins offers valuable insights into their function and activation mechanisms, aiding in predicting protein-ligand interactions, anticipating off-target effects, and facilitating the development of therapeutic agents. Numerous computational methods assessing global or local similarity in protein cavities have emerged, but their utilization is impeded by complexity, impractical automation for amino acid pattern searches, and an inability to evaluate the dynamics of scrutinized protein-ligand systems. Here, we present a general, automatic and unbiased computational pipeline, named VirtuousPocketome , aimed at screening huge databases of proteins for similar binding pockets starting from an interested protein-ligand complex. We demonstrate the pipeline’s potential by exploring a recently-solved human bitter taste receptor, i.e. the TAS2R46, complexed with strychnine. We pinpointed 145 proteins sharing similar binding sites compared to the analysed bitter taste receptor and the enrichment analysis highlighted the related biological processes, molecular functions and cellular components. This work represents the foundation for future studies aimed at understanding the effective role of tastants outside the gustatory system: this could pave the way towards the rationalization of the diet as a supplement to standard pharmacological treatments and the design of novel tastants-inspired compounds to target other proteins involved in specific diseases or disorders. The proposed pipeline is publicly accessible, can be applied to any protein-ligand complex, and could be expanded to screen any database of protein structures.

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Figures

Figure 1 Main interactions defining the three motifs for the bitter taste receptor interacting with strychnine. (A) Representative snapshot of the bitter-ligand complex, (B) PLIP interaction analysis identifying Hydrophobic Interaction (HI) and Saltbridge Interaction (SB), (C, D, E) site views of the three motifs identified. The bitter taste receptor is represented in grey, the strychnine in blue and the interacting residues in green (hydrophobic interactions) and purple (salt bridges).
Figure 1 Main interactions defining the three motifs for the bitter taste receptor interacting with strychnine. (A) Representative snapshot of the bitter-ligand complex, (B) PLIP interaction analysis identifying Hydrophobic Interaction (HI) and Saltbridge Interaction (SB), (C, D, E) site views of the three motifs identified. The bitter taste receptor is represented in grey, the strychnine in blue and the interacting residues in green (hydrophobic interactions) and purple (salt bridges).CC BY · PubMed Central
Figure 2 (A) Number of total structures in the original human proteome database and the number of selected hits from the similarity search and the subsequent multi-step filtering. (B) Binding site view of the strychnine bound to the best hit (PDB: 3A4S) according to the docking score at the end of the multi-step filtering process. Protein is rendered in grey, strychnine in blue, residues in the original motif of the bitter taste receptor in red and matching residues in the 3A4S structure in violet.
Figure 2 (A) Number of total structures in the original human proteome database and the number of selected hits from the similarity search and the subsequent multi-step filtering. (B) Binding site view of the strychnine bound to the best hit (PDB: 3A4S) according to the docking score at the end of the multi-step filtering process. Protein is rendered in grey, strychnine in blue, residues in the original motif of the bitter taste receptor in red and matching residues in the 3A4S structure in violet.CC BY · PubMed Central
Figure 3 Bar plots representing the best 5 retrieved GO terms for each category in the third level of the GO hierarchy relative to Biological Processes (BP), Molecular Functions (MF) and Cellular Components (CC).
Figure 3 Bar plots representing the best 5 retrieved GO terms for each category in the third level of the GO hierarchy relative to Biological Processes (BP), Molecular Functions (MF) and Cellular Components (CC).CC BY · PubMed Central
Figure 4 Flow Chart of the overall workflow of VirtuousPocketome.
Figure 4 Flow Chart of the overall workflow of VirtuousPocketome.CC BY · PubMed Central

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Metadata

Authors
Pallante, L., Cannariato, M., Androutsos, L., Zizzi, E. A., Bompotas, A., Hada, X., Grasso, G., Kalogeras, A., Mavroudi, S., di Benedetto, G., Theofilatos, K., & Deriu, M. A.
Affiliations
  • Politecnico di Torino (IT)
  • Industrial Systems Institute (GR)
  • University of Applied Sciences and Arts of Southern Switzerland (CH)
  • University of Patras (GR)
Corresponding author
Deriu, Marco A.
ORCID
Venue
Scientific Reports
Publisher
openRxiv
Published
2023-12-13
Volume
14
Issue
1
Pages
6296-6296
ISSN
2045-2322 (ISSN-L)
DOI
10.1101/2023.12.12.571207
PMC
PMC10943019
OpenAlex
W4392847330
Cited by
12
References
1
Citations by year
2026: 1 · 2025: 6 · 2024: 5
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PORTO@Iris (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • European Commission (872181, HORIZON2020)
  • H2020 Marie Skłodowska-Curie Actions (872181)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
protein pockets, protein-ligand complex, binding site similarity, protein structure comparison, strychnine, off-target effects
MeSH terms
Binding Sites, Humans, Ligands, Protein Binding, Proteins, Taste, Taste Buds

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Pallante, L., Cannariato, M., Androutsos, L., Zizzi, E. A., Bompotas, A., Hada, X., Grasso, G., Kalogeras, A., Mavroudi, S., di Benedetto, G., Theofilatos, K., & Deriu, M. A. (2023). VirtuousPocketome: A Computational Tool for Screening Protein-ligand Complexes to Identify Similar Binding Sites. Scientific Reports. https://doi.org/10.1101/2023.12.12.571207