Chemistry Reference
In-Depth Information
There was recently reported [411] a research work on binding estimation after refinement, a new automated
procedure for the refinement and rescoring of docked ligands in virtual screening. BEAR (Binding estimation after
refinement) is reportedly a novel automated computational procedure suitable for correcting and overcoming
limitations of docking procedures, such as the generation of unreasonable ligand conformations and poor scoring
function, which uses molecular dynamics simulation followed by MM-PBSA and MM-GBSA binding free energy
estimates as tools to refine and rescore the structures obtained from docking virtual screenings. As binding
estimation after refinement relies on molecular dynamics, the procedure can be adjusted to the needs of the end-user
in terms of computational time and the desired accuracy. Binding estimation after refinement and re-scoring, in a
validation test, resulted in a significant enrichment of known ligands among top scoring compounds compared with
the original docking results. After refinement, binding estimation has direct and straightforward application in
virtual screening for correcting both false-positive and false-negative hits, which should facilitate more reliable
selection of biologically active molecules [411-419].
An investigation of flexible protein-ligand docking [420] was recently reported. The new simulated annealing
protocol termed disrupted velocity simulated annealing (DIVE-SA) outperformed the replica-exchange method and
the traditional simulated annealing method in identifying correct docking poses. Atomic velocities were reassigned
periodically to encourage the system to sample a large conformational space. Scaling potential energy surfaces
reduces structural transition barriers which could further facilitate docking. The DIVE-SA method was evaluated on
its ability to perform flexible ligand-flexible protein docking. To reduce computational time and to avoid possible
unphysical structural changes resulting from the use of nonoptimal force fields, a soft restraint was applied to keep
the root-mean-square-deviation (RMSD) between instantaneous protein structures and a chosen reference structure
small. Their work demonstrates the important role that flexibility plays in accepting different ligands and should
profitably not be restrained in molecular docking so that more diverse ligands can be studied [94,420-426].
A novel visualization tool for the analysis and comparison of molecular docking (PosDock) [427] which processes a
docking results database and displays an interactive pseudo-3D snapshot of multiple ligand docking poses such that
their docking energies and docking poses are visually encoded for rapid assessment. The docking energies are
represented by a transparency scale whereas the docking poses are visually encoded by a color scale[ 427-429].
A study of assessment of scaffold hopping efficiency by use of molecular interaction fingerprints was recently
reported [97] whereas a novel scoring algorithm based on molecular interaction fingerprints (IFPs) was comparatively
evaluated in its scaffold hopping efficiency against four virtual screening standards (Glide, XP, Gold, ROCS and a
Bayesian classifier). Decoy databases for the targets under examination were obtained from the Directory of Useful
Decoys and were further enriched with approximately 5% of active ligands. Structure and ligand-based methods were
used to generate the ligand poses and a Tanimoto metric was chosen for the calculation of the similarity interaction
fingerprint between the reference ligand and the screening database whose enrichments were found to depend on the
pose generator algorithm. In spite of these dependencies enrichments using molecular IFPs were reportedly
comparable to those obtained with GlideXP, Gold, ROCS and the Bayesian classifier [97, 430-441].
Recent work have emphasized the importance of rescoring docking hit lists for model cavity sites. The strategy is to
rescore top-ranked docked molecules using a better but slower method such as molecular mechanics-generalized
Born surface area (MM-GBSA) techniques. These more physically realistic methods have improved models for
solvation, electrostatic interactions and conformational changes [442]
Recent work reports a computation methodology, which leads to the ability to partition the Gibb's free energy for
the complexation reaction of aromatic drug molecules with DNA. Using this approach, it is now possible to
calculate the absolute values of the energy contributions of various physical factors to the DNA binding process,
whose summation gives a value that is reasonably close to the experimentally measured Gibb's free energy of
binding. Application of the methodology to binding of various aromatic drugs with DNA can provide answers
regarding the main contributors to the stabilization of aromatic ligand-DNA complexes [443].
A recent work introduces CONFIRM (connecting fragments found in receptor molecules whereas a pre-prepared
library of bridges is searched to extract those which match a search criterion derived from known experimental or
computational binding information about fragment molecules within a target binding site. The resulting bridge 'hits'
