Development of high performance structure and ligand based virtual screening techniques

Abstract

Virtual Sreening (VS) is an in silico technique for drug discovery. An overview of VS methods is given and is seen to be approachable from two sides: structure based and ligand based. Structure based virtual screening uses explicit knowledge of the target receptor to suggest candidate receptor-ligand complexes. Ligand based virtual screening can infer required characteristics of binders from known ligands. A consideration for all virtual screening techniques is the amount of computing time required to arrive at a solution. For this reason, techniques of high performance computing have been applied to both the structural and ligand based approaches. A proven structure based virtual screening code LIDAEUS (Ligand Discovery At Edinburgh University) has been ported and parallelised to a massively parallel computing platform, the University of Edinburgh’s IBM Bluegene/l, consisting of 2,048 processor cores. A challenge in achieving scaling to such a large number of processors required implementation of a minimal communication parallel sort algorithm. Parallel efficiencies achieved within this parallelisation exceeded 99%, confirming that a near optimum strategy has been followed and capacity for running the code on a greater number of processors exists. This implementation of the program has been successfully used with a number of protein targets. The development of a new ligand based virtual screening code has been completed. The program UFSRAT (Ultra Fast Shape Recognition with Atom Types) takes the features of known binders and suggests molecules which will be able to make similar interactions. This similarity method is both fast (1 million molecules per hour per processor) and independent of input orientation. Along with UFSRAT, some other methods (VolRAT and UFSRGraph) based on UFSRAT have been developed, addressing different approaches to ligand based virtual screening. UFSRAT as an approach to discovering novel protein-ligand complexes has been validated with the discovery of a number of inhibitors for 11β-Hydroxysteroid Dehydrogenase type 1 and FK binding protein 12.