IsoCleft Finder - a Web-based Tool for the Detection and Analysis of Protein Binding-site Geometric and Chemical Similarities

Overview

Journal F1000Res

Specialties Biomedical Engineering
Science

Date 2014 Feb 25

PMID 24555058

Citations 8

Authors

Natalja Kurbatova

Matthieu Chartier

Maria Ines Zylber

Rafael Najmanovich

Affiliations

Soon will be listed here.

Abstract

IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code) combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity) and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder.

Citing Articles

VirtuousPocketome: a computational tool for screening protein-ligand complexes to identify similar binding sites.

Pallante L, Cannariato M, Androutsos L, Zizzi E, Bompotas A, Hada X Sci Rep. 2024; 14(1):6296.

PMID: 38491261 PMC: 10943019. DOI: 10.1038/s41598-024-56893-7.

A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs).

Ehrt C, Brinkjost T, Koch O PLoS Comput Biol. 2018; 14(11):e1006483.

PMID: 30408032 PMC: 6224041. DOI: 10.1371/journal.pcbi.1006483.

Ranking Enzyme Structures in the PDB by Bound Ligand Similarity to Biological Substrates.

Tyzack J, Fernando L, Ribeiro A, Borkakoti N, Thornton J Structure. 2018; 26(4):565-571.e3.

PMID: 29551288 PMC: 5890617. DOI: 10.1016/j.str.2018.02.009.

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

Chartier M, Morency L, Zylber M, Najmanovich R BMC Pharmacol Toxicol. 2017; 18(1):18.

PMID: 28449705 PMC: 5408384. DOI: 10.1186/s40360-017-0128-7.

IsoMIF Finder: online detection of binding site molecular interaction field similarities.

Chartier M, Adriansen E, Najmanovich R Bioinformatics. 2015; 32(4):621-3.

PMID: 26504139 PMC: 4743630. DOI: 10.1093/bioinformatics/btv616.

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