ElectroShape: fast molecular similarity calculations incorporating shape, chirality and electrostatics.
We present ElectroShape, a novel ligand-based virtual screening method, that combines shape and electrostatic information into a single, unified framework. Building on the ultra-fast shape recognition (USR) approach for fast non-superpositional shape-based virtual screening, it extends the method by representing partial charge information as a fourth dimension. It also incorporates the chiral shape recognition (CSR) method, which distinguishes enantiomers. It has been validated using release 2 of the Directory of useful decoys (DUD), and shows a near doubling in enrichment ratio at 1% over USR and CSR, and improvements as measured by Receiver Operating Characteristic curves. These improvements persisted even after taking into account the chemotype redundancy in the sets of active ligands in DUD. During the course of its development, ElectroShape revealed a difference in the charge allocation of the DUD ligand and decoy sets, leading to several new versions of DUD being generated as a result. ElectroShape provides a significant addition to the family of ultra-fast ligand-based virtual screening methods, and its higher-dimensional shape recognition approach has great potential for extension and generalisation.
Armstrong
M Stuart
MS
InhibOx, Pembroke House, 36-37 Pembroke Street, Oxford OX11BP, UK. stuart.armstrong@inhibox.com
Morris
Garrett M
GM
Finn
Paul W
PW
Sharma
Raman
R
Moretti
Loris
L
Cooper
Richard I
RI
Richards
W Graham
WG
D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D013237:Stereoisomerism
D008024:Ligands