Title: Development and application of QM/MM calculations for fragment-based drug design
Funder: Medical Research Council

Abstract: Fragment-based drug design, FBDD, is a highly promising novel approach for identifying lead compounds in a drug development programme10. It therefore lies firmly within one of the 10 MRC-identified health research opportunities for focusing strategic research, namely ?Development of new interventions?. FBDD offers efficient screening of chemical space so that higher hit rates are obtained in the initial phases and through careful attention to molecular properties the resulting drug candidates should have less chance of failure later in the process. However, FBDD also poses difficult biophysical and structural problems that need to be addressed, hence the strategic need for this proposal. The academic partner has current BBSRC funding to develop quantum mechanics (QM) based QM/MM methods that include molecular mechanics (MM) polarization. He has plans for other significant improvements to correctly address the steric repulsion between drug and enzyme using exponential repulsion (which is essential for success in crystal structure prediction11) rather than the computationally expedient r-12 repulsion. The industrial partner has a strong development interest in FBDD and is interested in using QM/MM to address the structural demands of FBDD since current docking methods are unreliable and the interpretation of X-ray structures of bound fragments can be ambiguous. The interchange enabled by this programme, will not only result in the development of new tools to underpin basic FBDD research, but also offers the potential to impact industrial and academic scientists in both institutions. Specific research goals include (i) a thorough survey of the usefulness of QM/MM in virtual screening. (ii) An analysis of the best way in which QM/MM with MM polarization can be used in virtual screening. (iii) An investigation of the use of realistic repulsion in virtual screening. (iv) An investigation in the use of QM/MM, in combination with the proposed improvements, in interpreting ambiguous X-ray crystal structures. The applicants have shared research goals as the industrial partner is interested in being able to apply efficient software to FBDD while the academic partner is interested in developing relevant computational methods that can be applied to the problem of improving the quality of life. 9. Maurer, RI; Blower, PJ; Dilworth, JR; Reynolds, CA; Zheng, YF; Mullen, GED Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone) radiopharmaceuticals. J. Med. Chem. 2002, 45, 1420-1431. 10. Congreve, M; Chessari, G; Tisi, D; Woodhead, AJ. Recent developments in fragment-based drug discovery. J. Med. Chem 2008, 51, 3661-3680. 5 11. Misquitta, AJ; Welch, GWA; Stone, AJ; Price, S. L. A first principles prediction of the crystal structure of C6Br2ClFH2. Chem. Phys. Lett. 2008, 456, 105-109. 12. Jorgensen, WL Special issue on polarization. J. Chem. Theory Comput. 2007, 3, 1877. 13. Mura, ME; Knowles, PJ; Reynolds, CA Accurate numerical determination of Kohn- Sham potentials from electronic densities .1. Two-electron systems J. Chem. Phys. 1997, 106, 9659-9667.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE