ElectroShape: fast molecular similarity calculations incorporating shape,chirality and electrostatics |
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Authors: | M Stuart Armstrong Garrett M Morris Paul W Finn Raman Sharma Loris Moretti Richard I Cooper W Graham Richards |
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Institution: | (1) InhibOx, Pembroke House, 36-37 Pembroke Street, Oxford, OX1 1BP, UK;(2) Department of Chemistry, InhibOx Laboratory, University of Oxford, Pembroke House, 36-37 Pembroke Street, Oxford, OX1 1BP, UK |
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Abstract: | 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. |
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