3D flexible alignment using 2D maximum common substructure: dependence of prediction accuracy on target-reference chemical similarity

J Chem Inf Model. 2014 Jul 28;54(7):1850-63. doi: 10.1021/ci500006d. Epub 2014 Jun 23.


A protein-bound conformation of a target molecule can be predicted by aligning the target molecule on the reference molecule obtained from the 3D structure of the compound-protein complex. This strategy is called "similarity-based docking". For this purpose, we develop the flexible alignment program fkcombu, which aligns the target molecule based on atomic correspondences with the reference molecule. The correspondences are obtained by the maximum common substructure (MCS) of 2D chemical structures, using our program kcombu. The prediction performance was evaluated using many target-reference pairs of superimposed ligand 3D structures on the same protein in the PDB, with different ranges of chemical similarity. The details of atomic correspondence largely affected the prediction success. We found that topologically constrained disconnected MCS (TD-MCS) with the simple element-based atomic classification provides the best prediction. The crashing potential energy with the receptor protein improved the performance. We also found that the RMSD between the predicted and correct target conformations significantly correlates with the chemical similarities between target-reference molecules. Generally speaking, if the reference and target compounds have more than 70% chemical similarity, then the average RMSD of 3D conformations is <2.0 Å. We compared the performance with a rigid-body molecular alignment program based on volume-overlap scores (ShaEP). Our MCS-based flexible alignment program performed better than the rigid-body alignment program, especially when the target and reference molecules were sufficiently similar.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclohexanes / chemistry
  • Drug Discovery
  • Models, Molecular*
  • Molecular Conformation


  • Cyclohexanes
  • Cyclohexane