Computational solvent mapping of proteins employs molecular probes to identify binding hot spots on the protein surface. Analogously to crystal solvent mapping and SAR by NMR, these hot spots found with solvent and fragment-sized molecules correspond to the most important locations for binding of small molecules. The diversity of fragments within a hot spot is also a strong predictor of the ability to develop a strong binder for a particular binding site, providing guidance for target selection and development of leads.
By analyzing proteins computationally, choices based on well-established FBDD principles made me made much more quickly and cheaply than with the analogous experimental methods, allowing high throughput prediction of binding to a selection of possible targets and critical guidance in optimization of molecules.
Acpharis Staff Publications using Computational Solvent Mapping
- Hall DR, Grove LE, Yueh C, Ngan CH, Kozakov D, Vajda S. 2011. Robust Identification of Binding Hot Spots Using Continuum Electrostatics: Application to Hen Egg-White Lysozyme. Journal of the American Chemical Society. 133(51):20668-20671.
- Kozakov D, Hall DR, Chuang G-Y, Cencic R, Brenke R, Grove LE, Beglov D, Pelletier J, Whitty A, Vajda S. 2011. Structural conservation of druggable hot spots in protein-protein interfaces. Proceedings of the National Academy of Sciences. 108(33):13528-13533.
- Cencic R, Hall DR, Robert F, Du Y, Min J, Li L, Qui M, Lewis I, Kurtkaya S, Dingledine R et al.. 2011. Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proceedings of the National Academy of Sciences of the United States of America. 108(3):1046-51.
- Chuang G-Y, Kozakov D, Brenke R, Beglov D, Guarnieri F, Vajda S. 2009. Binding Hot Spots and Amantadine Orientation in the Influenza A Virus M2 Proton Channel. Biophysical Journal. 97(10):2846-2853.