ProBiS-Database: Precalculated Binding Site Similarities and Local Pairwise Alignments of PDB Structures

Konc, Janez; Česnik, Tomo; Konc, Joanna Trykowska; Penca, Matej; Janežič, Dušanka

doi:10.1021/ci2005687

Cited by 51 publications

(64 citation statements)

References 27 publications

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“…The score is then standardized by Z-Score using precalculated alignment scores for all possible non-redundant Protein Data Bank (PDB) structure pairs. 20 CF-based alignment and scoring have a merit in that the CFs assigned in the structures are real interaction points for molecular recognition, but this approach requires more computational cost than Ca atom-based one due to a larger number of the structure-representing points in the alignment process. iAlign 21 and APoc 22 are computational methods for the structure alignment of protein-protein interfaces and protein pockets, respectively.…”

Section: Introductionmentioning

confidence: 99%

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

Lee

2016

Protein Science

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Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G-LoSA. G-LoSA aligns protein local structures in a sequence order independent way and provides a GA-score, a chemical feature-based and size-independent structure similarity score. Our benchmark validation shows the robust performance of G-LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure-centric comparative biology studies. In particular, G-LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of GLoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer-aided drug design. We hope that G-LoSA can be a useful computational method for exploring interesting biological problems through large-scale comparison of protein local structures and facilitating drug discovery research and development. G-LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/.

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Section: Introductionmentioning

confidence: 99%

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

Lee

2016

Protein Science

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“…Within each cluster obtained in Step 2, we compared each pair of binding sites (all against all) using ProBiS, and calculated their pairwise z-scores. [14] Then we clustered binding sites within each sequence identity cluster and obtained around 11.000 binding site clusters. Each such binding site cluster contained from a few to many thousands of binding sites.…”

Section: Binding Sites Data Preparationmentioning

confidence: 99%

“…[8][9][10][11][12] In this work, we developed a unique knowledgebased method to identify possible bioisosteric or scaffold hopping replacements for small molecules. We find bioisosteric replacements based on local binding site alignments using the ProBiS algorithm, [13][14][15] which enables finding bioisosterically replaceable fragments even in distantly related proteins. ProBiS superimposes binding sites and not entire protein structures (folds) nor protein sequences and seeks for locally similar spatial arrangements of physicochemically similar surface functional groups.…”

Section: Introductionmentioning

confidence: 99%

“…The process of identification of possible bioisosteric replacements was started using the ProBiS algorithm, [13][14][15] with which we superimposed the holo protein structures from the Protein Data Bank (PDB) containing co-crystallized small ligands. We compared and aligned binding sites that contained co-crystallized ligands; we superimposed the binding sites that had similar three-dimensional amino acid residue arrangements.…”

Section: Introductionmentioning

confidence: 99%

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Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Lešnik¹,

Konc²,

Janežič³

2016

Croat. Chem. Acta

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Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate -a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor.

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“…[2][3][4][5] The ProBiS algorithm of Konc and Janezic [6] belongs to the latter class of algorithms and detects pairwise local similarities in proteins by computing the similarity of protein graphs, which are representations of specific proteins. It runs in the ProBiS web server [7] at http:// probis.cmm.ki.si and the parallel version was used to create the ProBiS-Database, [8] a repository of over 420 million precalculated binding site similarities and local pairwise alignments of protein database (PDB) structures at http://probis.cmm.ki.si/ database. Despite the complexity of comparing entire protein structures, ProBiS has demonstrated its ability to find intricate similar three-dimensional patterns in sites involved in binding of small molecules, ions, proteins, or nucleic acids [6] ; its compelling advantages are speed and the ever-increasing availability of appropriate protein structures.…”

Section: Introductionmentioning

confidence: 99%

Parallel‐ProBiS: Fast parallel algorithm for local structural comparison of protein structures and binding sites

et al. 2012

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The ProBiS algorithm performs a local structural comparison of the query protein surface against the nonredundant database of protein structures. It finds proteins that have binding sites in common with the query protein.Here, we present a new parallelized algorithm, Parallel-ProBiS, for detecting similar binding sites on clusters of computers. The obtained speedups of the parallel ProBiS scale almost ideally with the number of computing cores up to about 64 computing cores. Scaling is better for larger than for smaller query proteins. For a protein with almost 600 amino acids, the maximum speedup of 180 was achieved on two interconnected clusters with 248 computing cores. Source code of Parallel-ProBiS is available for download free for academic users at

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ProBiS-Database: Precalculated Binding Site Similarities and Local Pairwise Alignments of PDB Structures

Cited by 51 publications

References 27 publications

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Parallel‐ProBiS: Fast parallel algorithm for local structural comparison of protein structures and binding sites

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