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A fast topological analysis algorithm for large-scale similarity evaluations of ligands and binding pockets.

ElGamacy M, Van Meervelt L - J Cheminform (2015)

Bottom Line: The method remarkably shows potential for application for scaffold hopping purposes.It also opens new frontiers in the areas of ligand-mediated protein connectivity, ligand-based molecular phylogeny, target fishing, and off-target predictions.Graphical abstract:A novel molecular topology comparison method based on a combined shape distribution and charge binning scheme is presented.

View Article: PubMed Central - PubMed

Affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany ; Biomolecular Architecture, Chemistry Department, KU Leuven, Celestijnenlaan 200F, box 2404, 3001 Leuven (Heverlee), Belgium.

ABSTRACT

Motivation: With the rapid increase of the structural data of biomolecular complexes, novel structural analysis methods have to be devised with high-throughput capacity to handle immense data input and to construct massive networks at the minimal computational cost. Moreover, novel methods should be capable of handling a broad range of molecular structural sizes and chemical natures, cognisant of the conformational and electrostatic bases of molecular recognition, and sufficiently accurate to enable contextually relevant biological inferences.

Results: A novel molecular topology comparison method was developed and tested. The method was tested for both ligand and binding pocket similarity analyses and a PDB-wide ligand topological similarity map was computed.

Conclusion: The unprecedentedly wide scope of ligand definition and large-scale topological similarity mapping can provide very robust tools, of performance unmatched by the present alignment-based methods. The method remarkably shows potential for application for scaffold hopping purposes. It also opens new frontiers in the areas of ligand-mediated protein connectivity, ligand-based molecular phylogeny, target fishing, and off-target predictions. Graphical abstract:A novel molecular topology comparison method based on a combined shape distribution and charge binning scheme is presented.

No MeSH data available.


Related in: MedlinePlus

Two heat map strips of dissimilarity scores using the original conformation of quercetin from 1H1I (right), and six generated conformations (left) against the PDB ligands. The strips enlists the top 50 similar ligands (corresponding colour legends shown), upper left shows the chemical structure of quercetin, the green dot marks hits with flavonoid scaffold. The colour legend represents the dissimilarity score (d) scale (see “Methods” section).
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Fig1: Two heat map strips of dissimilarity scores using the original conformation of quercetin from 1H1I (right), and six generated conformations (left) against the PDB ligands. The strips enlists the top 50 similar ligands (corresponding colour legends shown), upper left shows the chemical structure of quercetin, the green dot marks hits with flavonoid scaffold. The colour legend represents the dissimilarity score (d) scale (see “Methods” section).

Mentions: First, two searches were conducted using as query the quercetin structure as obtained from the crystal structure of quercetin complexed with quercetin-2,3-dioxygenase (PDB: 1H1I) and six conformers sampled from the latter. Results were sorted according to the dissimilarity score in ascending order (Fig. 1). This was a control case with one rotatable bond to demonstrate the effect of using multiple conformers.Fig. 1


A fast topological analysis algorithm for large-scale similarity evaluations of ligands and binding pockets.

ElGamacy M, Van Meervelt L - J Cheminform (2015)

Two heat map strips of dissimilarity scores using the original conformation of quercetin from 1H1I (right), and six generated conformations (left) against the PDB ligands. The strips enlists the top 50 similar ligands (corresponding colour legends shown), upper left shows the chemical structure of quercetin, the green dot marks hits with flavonoid scaffold. The colour legend represents the dissimilarity score (d) scale (see “Methods” section).
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4631714&req=5

Fig1: Two heat map strips of dissimilarity scores using the original conformation of quercetin from 1H1I (right), and six generated conformations (left) against the PDB ligands. The strips enlists the top 50 similar ligands (corresponding colour legends shown), upper left shows the chemical structure of quercetin, the green dot marks hits with flavonoid scaffold. The colour legend represents the dissimilarity score (d) scale (see “Methods” section).
Mentions: First, two searches were conducted using as query the quercetin structure as obtained from the crystal structure of quercetin complexed with quercetin-2,3-dioxygenase (PDB: 1H1I) and six conformers sampled from the latter. Results were sorted according to the dissimilarity score in ascending order (Fig. 1). This was a control case with one rotatable bond to demonstrate the effect of using multiple conformers.Fig. 1

Bottom Line: The method remarkably shows potential for application for scaffold hopping purposes.It also opens new frontiers in the areas of ligand-mediated protein connectivity, ligand-based molecular phylogeny, target fishing, and off-target predictions.Graphical abstract:A novel molecular topology comparison method based on a combined shape distribution and charge binning scheme is presented.

View Article: PubMed Central - PubMed

Affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany ; Biomolecular Architecture, Chemistry Department, KU Leuven, Celestijnenlaan 200F, box 2404, 3001 Leuven (Heverlee), Belgium.

ABSTRACT

Motivation: With the rapid increase of the structural data of biomolecular complexes, novel structural analysis methods have to be devised with high-throughput capacity to handle immense data input and to construct massive networks at the minimal computational cost. Moreover, novel methods should be capable of handling a broad range of molecular structural sizes and chemical natures, cognisant of the conformational and electrostatic bases of molecular recognition, and sufficiently accurate to enable contextually relevant biological inferences.

Results: A novel molecular topology comparison method was developed and tested. The method was tested for both ligand and binding pocket similarity analyses and a PDB-wide ligand topological similarity map was computed.

Conclusion: The unprecedentedly wide scope of ligand definition and large-scale topological similarity mapping can provide very robust tools, of performance unmatched by the present alignment-based methods. The method remarkably shows potential for application for scaffold hopping purposes. It also opens new frontiers in the areas of ligand-mediated protein connectivity, ligand-based molecular phylogeny, target fishing, and off-target predictions. Graphical abstract:A novel molecular topology comparison method based on a combined shape distribution and charge binning scheme is presented.

No MeSH data available.


Related in: MedlinePlus