Journal of Computer-Aided Molecular Design

, Volume 18, Issue 3, pp 189–208 | Cite as

Validation of an empirical RNA-ligand scoring function for fast flexible docking using RiboDock®

  • S. David Morley
  • Mohammad Afshar
Article

Abstract

We report the design and validation of a fast empirical function for scoring RNA-ligand interactions, and describe its implementation within RiboDock®, a virtual screening system for automated flexible docking. Building on well-known protein-ligand scoring function foundations, features were added to describe the interactions of common RNA-binding functional groups that were not handled adequately by conventional terms, to disfavour non-complementary polar contacts, and to control non-specific charged interactions. The results of validation experiments against known structures of RNA-ligand complexes compare favourably with previously reported methods. Binding modes were well predicted in most cases and good discrimination was achieved between native and non-native ligands for each binding site, and between native and non-native binding sites for each ligand. Further evidence of the ability of the method to identify true RNA binders is provided by compound selection (`enrichment factor') experiments based around a series of HIV-1 TAR RNA-binding ligands. Significant enrichment in true binders was achieved amongst high scoring docking hits, even when selection was from a library of structurally related, positively charged molecules. Coupled with a semi-automated cavity detection algorithm for identification of putative ligand binding sites, also described here, the method is suitable for the screening of very large databases of molecules against RNA and RNA-protein interfaces, such as those presented by the bacterial ribosome.

Abbreviations: ACD – Available Chemicals Directory; AMP – adenosine monophosphate; EF – enrichment factor; FMN – flavin mononucleotide; FRET – fluorescence resonance energy transfer; RMSD – root mean square deviation; TAR – trans-activation response element; Tat – transcriptional activator protein.

bacterial A-site cavity detection enrichment factor guanidine high throughput docking HIV-1 TAR RiboDock® RNA aptamer structure-based drug design virtual screening 

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Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • S. David Morley
    • 1
  • Mohammad Afshar
    • 1
  1. 1.RiboTargetsCambridgeshireUK
  2. 2.Enspiral Discovery LtdCambridgeUK
  3. 3.Ariana PharmaParis Cedex 15France

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