Protein pocket and ligand shape comparison and its application in virtual screening.

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Serval ID
serval:BIB_CEE455C0EFFA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protein pocket and ligand shape comparison and its application in virtual screening.
Journal
Journal of Computer-aided Molecular Design
Author(s)
Wirth M., Volkamer A., Zoete V., Rippmann F., Michielin O., Rarey M., Sauer W.H.
ISSN
1573-4951 (Electronic)
ISSN-L
0920-654X
Publication state
Published
Issued date
2013
Volume
27
Number
6
Pages
511-524
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Understanding molecular recognition is one major requirement for drug discovery and design. Physicochemical and shape complementarity between two binding partners is the driving force during complex formation. In this study, the impact of shape within this process is analyzed. Protein binding pockets and co-crystallized ligands are represented by normalized principal moments of inertia ratios (NPRs). The corresponding descriptor space is triangular, with its corners occupied by spherical, discoid, and elongated shapes. An analysis of a selected set of sc-PDB complexes suggests that pockets and bound ligands avoid spherical shapes, which are, however, prevalent in small unoccupied pockets. Furthermore, a direct shape comparison confirms previous studies that on average only one third of a pocket is filled by its bound ligand, supplemented by a 50 % subpocket coverage. In this study, we found that shape complementary is expressed by low pairwise shape distances in NPR space, short distances between the centers-of-mass, and small deviations in the angle between the first principal ellipsoid axes. Furthermore, it is assessed how different binding pocket parameters are related to bioactivity and binding efficiency of the co-crystallized ligand. In addition, the performance of different shape and size parameters of pockets and ligands is evaluated in a virtual screening scenario performed on four representative targets.
Keywords
Crystallography, X-Ray, Drug Discovery, Humans, Ligands, Models, Molecular, Protein Binding, Protein Conformation, Proteins/chemistry
Pubmed
Web of science
Open Access
Yes
Create date
10/09/2014 9:46
Last modification date
01/10/2019 7:19
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