Fulltext

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

Wirth, Matthias ; Volkamer, Andrea ; Zoete, Vincent ; Rippmann, Friedrich ; Michielin, Olivier ; Rarey, Matthias ; Sauer, Wolfgang

In: Journal of Computer-Aided Molecular Design, 2013, vol. 27, no. 6, p. 511-524

Ajouter à la liste personnelle
    Titre
    • Protein pocket and ligand shape comparison and its application in virtual screening
    Auteur
    • Wirth, Matthias. Computational Chemistry, Merck Serono S.A. Geneva, Chemin des Mines 9, 1202, Geneva, Switzerland
    • Volkamer, Andrea. Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146, Hamburg, Germany
    • Zoete, Vincent. Swiss Institute of Bioinformatics, Molecular Modelling Group, UNIL Sorge-Bâtiment Génopode, 1015, Lausanne, Switzerland
    • Rippmann, Friedrich. Global Computational Chemistry, Merck KGaA, Merck Serono, Frankfurter Str. 250, 64293, Darmstadt, Germany
    • Michielin, Olivier. Swiss Institute of Bioinformatics, Molecular Modelling Group, UNIL Sorge-Bâtiment Génopode, 1015, Lausanne, Switzerland
    • Rarey, Matthias. Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146, Hamburg, Germany
    • Sauer, Wolfgang. Computational Chemistry, Merck Serono S.A. Geneva, Chemin des Mines 9, 1202, Geneva, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Journal of Computer-Aided Molecular Design, 2013, vol. 27, no. 6, p. 511-524. Springer Netherlands
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:321238
    Summary
    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