Gwyn SkonePublications


Doctoral Thesis:

Stratagems for Effective Function Evaluation in Computational Chemistry
Oxford, 2010


Doing a Good Turn: The Use of Quaternions for Rotation in Molecular Docking
J. Chem. Inf. Model. 2013
Knowing When To Give Up: Early-Rejection Stratagems in Ligand Docking
J. Comput. Aided Mol. Des. 2009
Protein Structure Computation
Proc. FBIT 2007


Basic Strategies for Molecular Docking with Scoring Functions
German Conf. Bioinf. 2008


Knowing When To Give Up: Sensible Evaluation in Virtual Screening for Drug Discovery
OUCL Cakes Talk. 2008
Protein Structure Computation
Proc. OUCL PRG Student Conf. 2006

Stratagems for Effective Function Evaluation in Computational Chemistry

Gwyn Skone
DPhil (PhD) Thesis, University of Oxford, UK. 2010.

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Oxford University Research Archive entry page

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In recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a vast combinatorial range. This is particularly the case for protein-ligand docking, since proteins are sophisticated structures with complicated interactions for which either molecule might reshape itself. Even the very limited flexibility model to be considered here, using ligand conformation ensembles, requires six dimensions of exploration — three translations and three rotations — per rigid conformation. The functions for evaluating pose suitability can also be complex to calculate. Consequently, the programs being written for these biochemical simulations are extremely resource-intensive.

This work introduces a pure computer science approach to the field, developing techniques to improve the effectiveness of such tools. Their architecture is generalized to an abstract pattern of nested layers for discussion, covering scoring functions, search methods, and screening overall. Based on this, new stratagems for molecular docking software design are described, including lazy or partial evaluation, geometric analysis, and parallel processing implementation. In addition, a range of novel algorithms are presented for applications such as active site detection with linear complexity (PIES) and small molecule shape description (PASTRY) for pre-alignment of ligands. The various stratagems are assessed individually and in combination, using several modified versions of an existing docking program, to demonstrate their benefit to virtual screening in practical contexts. In particular, the importance of appropriate precision in calculations is highlighted.