Affinity prediction

A Hbasis functions provides K molecular orbitals, but lUJiW of these will not be occupied by smy electrons they are the virtual spin orbitals. If u c were to add an electron to one of these virtual orbitals then this should provide a means of calculating the electron affinity of the system. Electron affinities predicted by Konpman s theorem are always positive when Hartree-Fock calculations are used, because fhe irtucil orbitals always have a positive energy. However, it is observed experimentally that many neutral molecules will accept an electron to form a stable anion and so have negative electron affinities. This can be understood if one realises that electron correlation uDiild be expected to add to the error due to the frozen orbital approximation, rather ihan to counteract it as for ionisation potentials. 

Hansson T, J Mturelius and J Aqvist 1998. Ligand Binding Affinity Prediction by Linear InteracHor Energy Methods. Journal of Computer-Aided Molecular Design 12 27-35. 

T. Hansson, J. Marelius, and J. Aqvist, Ligand binding affinity prediction by linear... 

Kroeze, W. K., Hufeisen, S. J., Popadak, B. A. et al. HI-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28 519-526, 2003. 

Zamora, I., Oprea, T., Cruciani, G., Pastor, M., and Ungell, A.-L. Surface descriptors for protein-ligand affinity prediction. /. Med. Chem. 2003, 46, 25-33. 

As can be seen, generally all electron affinities predicted by ASCF are negative, indicating a more stable neutral system with respect to the anion. The inclusion of correlation via CCSD(T) and NOF approximates them to the available adiabatic experimental EAs, accordingly with the expected trend. The EAs tend to increase in moving from ACCSD(T) to ANOF and then from ANOF to the experiment. It should be noted that the NH anion is predicted to be unbound by CCSD(T), whereas the positive vertical EA value via NOE corresponds to the bound anionic state. 

Rolland, C., Gozalbes, R., Nicolai, E., Paugam, M.-F., Coussy, L, Barbosa, F., Horvath, D. and Revah, F. (2005) G-protein-coupled receptor affinity prediction based on the use of a profiling dataset QSAR design, synthesis, and experimental validation. Journal of Medicinal Chemistry, 48 (21), 6563-6574. 

So S-S. and M. Karplus (1999). A comparative study of ligand-receptor complex binding affinity prediction methods based on glycogen phosphorylase inhibitors. Journal of Computer Aided Molecular Design 13 243-258. 

Example of affinity prediction of 5-HT7 antagonists (Lopez-Rodrfguez et al., 2000 and 2003)... 

Wang, R. X., Lai, L. H., and Wang, S. M. (2002) Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J. Comput. Aided Mol. Des. 16,11-26. 

Affinity prediction using manual docking in combination with energy minimizations and lD-QSARs. 

Almlof M, Brandsdal BO, Aqvist J (2004) Binding affinity prediction with different force fields examination of the linear interaction energy method. J Comput Chem 25(10) 1242-1254... 

Table 13.5 summarizes the priority setting results for the two data sets using the NCTR Four-Phase system. When only the Phase I and II protocols are used, the system dramatically reduced the number of potential estrogens by some 80 to 85%, demonstrating its effectiveness in eliminating these most unlikely ER binders from further expensive experimentation. The Phase III CoMFA model further reduces the data size by about 5 to 10%. More importantly, the quantitative binding affinity prediction from Phase III provides an important rank-order value for priority setting. 

Dyguda E, Grembecka J, Sokalski WA, Leszczynski J (2004) Origins of the activity of PAL and LAP enzyme inhibitors Toward ab initio binding affinity prediction. J Am Chem Soc 127 1658-1659... 

Wess G (2002) How to escape the bottleneck of medicinal chemistry. Drug Disc Today 7 533-535 Zamora I, Oprea T, Cruciani G et al. (2003) Surface descriptors for protein-ligand affinity prediction. J Med Chem 46 25-33... 

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