GPhL Cambridge, UK

Role and contribution

Global Phasing is an SME created by Dr. G. Bricogne under an agreement with the MRC Laboratory of Molecular Biology (Cambridge, UK). It is financed through an industrial research Consortium comprising all the major pharmaceutical companies and some of the new drug discovery companies. Its main activity is the development of phasing and refinement software for macromolecular crystallography. Its main products are : (1) SHARP for experimental phasing, using a maximum-likelihood method for refining heavy-atom parameters in the presence of phase uncertainty and its graphical user interface SUSHI which incorporates a powerful script for density modification using SOLOMON ; (2) autoSHARP, a system of scripts for automated structure solution from experimental phase information, using RANTAN for heavy-atom detection and scripts for driving ARP/wARP (Partners 7 and 8) in an optimal fashion ; (3) BUSTER for maximum-likelihood structure refinement, using the TNT refinement package of the US developers L. Ten Eyck and D. Tronrud and providing a maximum-entropy completion capability for partial models. The “production version” of Global Phasing’s software is distributed for free to academic institutions in the entire world. SHARP/autoSHARP is now installed on over 700 machines in over 500 academic laboratories. The recently released SHARP 2.0 is the outcome of 6 man-years of additional work, entirely financed by the pharmaceutical industry, on improving the speed and performance of the previous version. Speedup factors ranging from 15 (for small problems) to 200 (for large ones) have been achieved, as well as marked improvements in the final results. Through the development, testing and deployment of SHARP, BUSTER and autoSHARP over a period of almost 10 years, as well as through its industrial funding, this Partner has been in direct contact and interaction with the structure-based drug design groups in all the major pharmaceutical companies and the most prominent drug discovery startups in the world, and has acquired extensive experience in the computational aspects of phasing and refining difficult structures, and in high-throughput crystallographic methods of looking for weak ligands being tested as putative building blocks of drug candidates. VIZIER projects will be given access to the software and to this expertise through the hiring a full-time crystallographer capable of solving difficult structures with state-of the-art software.