Dataset Information

Application of 3D Zernike descriptors to shape-based ligand similarity searching.

ABSTRACT: BACKGROUND:The identification of promising drug leads from a large database of compounds is an important step in the preliminary stages of drug design. Although shape is known to play a key role in the molecular recognition process, its application to virtual screening poses significant hurdles both in terms of the encoding scheme and speed. RESULTS:In this study, we have examined the efficacy of the alignment independent three-dimensional Zernike descriptor (3DZD) for fast shape based similarity searching. Performance of this approach was compared with several other methods including the statistical moments based ultrafast shape recognition scheme (USR) and SIMCOMP, a graph matching algorithm that compares atom environments. Three benchmark datasets are used to thoroughly test the methods in terms of their ability for molecular classification, retrieval rate, and performance under the situation that simulates actual virtual screening tasks over a large pharmaceutical database. The 3DZD performed better than or comparable to the other methods examined, depending on the datasets and evaluation metrics used. Reasons for the success and the failure of the shape based methods for specific cases are investigated. Based on the results for the three datasets, general conclusions are drawn with regard to their efficiency and applicability. CONCLUSION:The 3DZD has unique ability for fast comparison of three-dimensional shape of compounds. Examples analyzed illustrate the advantages and the room for improvements for the 3DZD.

SUBMITTER: Venkatraman V

PROVIDER: S-EPMC2820497 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Application of 3D Zernike descriptors to shape-based ligand similarity searching.

Venkatraman Vishwesh V Chakravarthy Padmasini Ramji PR Kihara Daisuke D

Journal of cheminformatics 20091217

<h4>Background</h4>The identification of promising drug leads from a large database of compounds is an important step in the preliminary stages of drug design. Although shape is known to play a key role in the molecular recognition process, its application to virtual screening poses significant hurdles both in terms of the encoding scheme and speed.<h4>Results</h4>In this study, we have examined the efficacy of the alignment independent three-dimensional Zernike descriptor (3DZD) for fast shape ...[more]

PMID: 20150998

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Project description:Protein-protein interactions are a pivotal component of many biological processes and mediate a variety of functions. Knowing the tertiary structure of a protein complex is therefore essential for understanding the interaction mechanism. However, experimental techniques to solve the structure of the complex are often found to be difficult. To this end, computational protein-protein docking approaches can provide a useful alternative to address this issue. Prediction of docking conformations relies on methods that effectively capture shape features of the participating proteins while giving due consideration to conformational changes that may occur.We present a novel protein docking algorithm based on the use of 3D Zernike descriptors as regional features of molecular shape. The key motivation of using these descriptors is their invariance to transformation, in addition to a compact representation of local surface shape characteristics. Docking decoys are generated using geometric hashing, which are then ranked by a scoring function that incorporates a buried surface area and a novel geometric complementarity term based on normals associated with the 3D Zernike shape description. Our docking algorithm was tested on both bound and unbound cases in the ZDOCK benchmark 2.0 dataset. In 74% of the bound docking predictions, our method was able to find a near-native solution (interface C-alphaRMSD < or = 2.5 A) within the top 1000 ranks. For unbound docking, among the 60 complexes for which our algorithm returned at least one hit, 60% of the cases were ranked within the top 2000. Comparison with existing shape-based docking algorithms shows that our method has a better performance than the others in unbound docking while remaining competitive for bound docking cases.We show for the first time that the 3D Zernike descriptors are adept in capturing shape complementarity at the protein-protein interface and useful for protein docking prediction. Rigorous benchmark studies show that our docking approach has a superior performance compared to existing methods.

Project description:Structure-based virtual screening (SBVS) is a widely used method in silico drug discovery. It necessitates a receptor structure or binding site to predict the binding pose and fitness of a ligand. Therefore, the performance of the SBVS is affected by the protein conformation. The most frequently used method in SBVS is the protein-ligand docking program, which utilizes atomic distance-based scoring functions. Hence, they are highly prone to sensitivity towards variation in receptor structure, and it is reported that the conformational change significantly drops the performance of the docking program. To address the problem, we have introduced a novel program of SBVS, named PL-PatchSurfer. This program makes use of molecular surface patches and the Zernike descriptor. The surfaces of the pocket and ligand are segmented into several patches by the program. These patches are then mapped with physico-chemical properties such as shape and electrostatic potential before being converted into the Zernike descriptor, which is rotationally invariant. A complementarity between the protein and the ligand is assessed by comparing the descriptors and geometric distribution of the patches in the molecules. A benchmarking study showed that PL-PatchSurfer2 was able to screen active molecules regardless of the receptor structure change with fast speed. However, the program could not achieve high performance for the targets that the hydrogen bonding feature is important such as nuclear hormone receptors. In this paper, we present the newer version of PL-PatchSurfer, PL-PatchSurfer3, which incorporates two new features: a change in the definition of hydrogen bond complementarity and consideration of visibility that contains curvature information of a patch. Our evaluation demonstrates that the new program outperforms its predecessor and other SBVS methods while retaining its characteristic tolerance to receptor structure changes. Interested individuals can access the program at kiharalab.org/plps3.

Project description:BACKGROUND:The correct determination of protein-protein interaction interfaces is important for understanding disease mechanisms and for rational drug design. To date, several computational methods for the prediction of protein interfaces have been developed, but the interface prediction problem is still not fully understood. Experimental evidence suggests that the location of binding sites is imprinted in the protein structure, but there are major differences among the interfaces of the various protein types: the characterising properties can vary a lot depending on the interaction type and function. The selection of an optimal set of features characterising the protein interface and the development of an effective method to represent and capture the complex protein recognition patterns are of paramount importance for this task. RESULTS:In this work we investigate the potential of a novel local surface descriptor based on 3D Zernike moments for the interface prediction task. Descriptors invariant to roto-translations are extracted from circular patches of the protein surface enriched with physico-chemical properties from the HQI8 amino acid index set, and are used as samples for a binary classification problem. Support Vector Machines are used as a classifier to distinguish interface local surface patches from non-interface ones. The proposed method was validated on 16 classes of proteins extracted from the Protein-Protein Docking Benchmark 5.0 and compared to other state-of-the-art protein interface predictors (SPPIDER, PrISE and NPS-HomPPI). CONCLUSIONS:The 3D Zernike descriptors are able to capture the similarity among patterns of physico-chemical and biochemical properties mapped on the protein surface arising from the various spatial arrangements of the underlying residues, and their usage can be easily extended to other sets of amino acid properties. The results suggest that the choice of a proper set of features characterising the protein interface is crucial for the interface prediction task, and that optimality strongly depends on the class of proteins whose interface we want to characterise. We postulate that different protein classes should be treated separately and that it is necessary to identify an optimal set of features for each protein class.

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Application of 3D Zernike descriptors to shape-based ligand similarity searching.

Publications

Application of 3D Zernike descriptors to shape-based ligand similarity searching.

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