A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)

Giovanni Bottegoni, Irina Kufareva, Maxim Totrov, Ruben Abagyan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)


Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. We expanded a previously used diverse "cross-docking" benchmark to thirty ligand-protein pairs extracted from different crystal structures. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each 'gapped' version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each 'gapped' pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2 Å RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with ∼ 5 Å margin as used in most previous publications. The presented fully automated algorithm takes about 2 h per pose of a single processor time, requires only one pocket structure and no prior knowledge about the binding site location. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.

Original languageEnglish
Pages (from-to)311-325
Number of pages15
JournalJournal of Computer-Aided Molecular Design
Issue number5
Publication statusPublished - 1 May 2008
Externally publishedYes


  • Cross docking
  • Drug binding
  • ICM
  • Induced fit
  • Internal coordinate mechanics
  • Receptor flexibility
  • Scanning docking
  • Structure based drug design

ASJC Scopus subject areas

  • Molecular Medicine
  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Drug Discovery


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