Software tools for structure based rational drug design

摘要

Scientific advancements during the past two decades have altered the way pharmaceutical research produces new bio-active molecules. Traditional `trial and error' drug discovery efforts are gradually being replaced by structure based rational drug design. A key technique is the use of methods including X-ray crystallography and NMR for the determination of the 3-dimensional structure of a target protein followed by various modelling techniques for the design of small molecule ligands that could interact with the target structure. The first generation of the software tools were limited to energy calculations and molecular dynamics simulations based on simple force field models. More automated methods, like flexible ligand docking and de novo ligand design programs have emerged in the 90s. However, many of these software systems relied on stochastic algorithms to perform the search, effectively performing a computerised `trial and error' search. SimBioSys provides ligand design and docking tools that are systematic, exhaustive, rely on rational rules, heuristics and dynamic knowledge bases. The novel algorithms designed and optimised to solve the specific problems greatly outperform the general random methods. The presentation gives a brief overview of the efficient algorithms behind the SPROUT (de novo ligand design) and eHiTS (flexible ligand docking and virtual high throughput screening) software tools. Validation test results are presented to demonstrate the effectiveness of these tools for the solution of practical drug design problems.