Alessandro Contini
Department of Pharmaceutical Sciences, University of Milan
Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) are interesting techniques for drug design/discovery applications, but sometimes the correlation between predicted and experimental binding energies might result unsatisfactory.
The inclusion of explicit water molecules in MM-PBSA/GBSA binding energy predictions is controversial,1-4 and special care needs to be taken when selecting those waters to be included in the calculation. We found that the consideration of a hydration shell populated by a number of water residues (Nwat) between 30 and 70 can improve the correlation between MM-PBSA/GBSA calculated binding affinities and experimental activities, with a negligible increment of computational cost.5
In this workshop, we are going to see how to run MM-GBSA calculations including explicit waters, to estimate the relative free energies of binding for a selection of protein kinases inhibitors.
REFERENCES
1. Wong, S.; Amaro, R. E.; McCammon, J. A., J. Chem. Theory Comput. 2009, 5, 422-429.
2. Hayes, J. M.; Skamnaki, V. T.; Archontis, G.; Lamprakis, C.; Sarrou, J.; Bischler, N.; Skaltsounis, A.-L.; Zographos, S. E.; Oikonomakos, N. G., Proteins 2011, 79, 703-19.
3. Freedman, H.; Huynh, L. P.; Le, L.; Cheatham, I. I. I. T. E.; Tuszynski, J. A.; Truong, T. N., J. Phys. Chem. B 2010, 114, 2227-2237.
4. Checa, A.; Ortiz, A. R.; de Pascual-Teresa, B.; Gago, F., J. Med. Chem. 1997, 40 (25), 4136-45.
5. Maffucci, I.; Contini, A., J. Chem. Theory Comput. 2013, 9 (6), 2706-2717.
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