The CCDC, working in collaboration with the University of Sheffield and GlaxoSmithKline, have developed GOLD, one of the very first programs for docking ligands into proteins. Subsequently we have invested a very significant research effort to improve the quality of data that GOLD produces and, because this cannot be done without suitable tools, to develop the validation methods and datasets required to prove true advances have been made. As a result of this research the breadth of application of the GOLD software has been greatly enhanced to take into account water molecules in binding sites, metal centres and flexible side chains. An important research component is the use of knowledge based methodology, utilising information from the Cambridge Structural Database to improve the geometries of ligand poses. We have also researched and continue to research methods of analysis of large volumes virtual screening data.
Also of relevance in molecular docking is the CCDC’s research in understanding intermolecular interactions of small molecules (encapsulated in the IsoStar system) and extending this to the interactions one sees between ligand and proteins (SuperStar). The research that led to the development of these tools revealed much about the prevalence of particular molecular recognition motifs.
Docking science is a rapidly evolving field and many different programs have been written. The GOLD program remains a world leading docking tool widely used by many researchers in academia and industry. Current research efforts are aimed at achieving three goals. Firstly, the appropriate incorporation of protein flexibility in docking is an important and as yet unrealised goal. We have investigated an ensemble approach where a number of key static representations of a protein structure are selected and docked against. The research encompasses both the protein model generation stage and the docking stage. Secondly we wish to develop methodologies that can maximise the success of use of GOLD as a virtual screening tool for the discovery of novel drug leads. We are undertaking collaborative research targeting a structure-based drug target of mycobacterium tuberculosis using GOLD for virtual screening. Key to this is the development of different post docking analysis protocols. Thirdly we have initiated studies in use of docking in multi-component crystalline materials design.