Automated search strategies

Rather than compare only the lowest energy structures of the competing diastereomeric complexes, Lipkowitz computes a statistically averaged interaction energy, E, as in eqn. 13. 

The terms within the parentheses are simply probabilities. The first term is the probability of finding the CSP in a given conformational state, the second term is the probability that the analyte is in a particular conformation and the last term is the probability that the two molecules are positioned and oriented in a particular way with respect to each other. Note that because the authors locate all the minima on the complex s intermolecular potential energy surfaces they can derive the entropy of the system as well. Therefore E is actually a good representation of the macroscopic free energy of interaction, which in this case corresponds to a Gibbs free energy. 

Because of the large number of configurations sampled the authors restricted themselves to empirical force fields for computing the intermolecular energies. This is not only faster than a quantum-based approach but it is better because empirical force fields reproduce more accurately the dispersion forces between molecules than do quantum methods at a Hartree-Fock level of theory. Because empirical force fields are not particularly accurate or precise, the authors decided to treat the R and S analytes in an identical manner as explained above. This way, if the force field underestimates, say, hydrogen bonding and overestimates electrostatics, the errors should be nearly the same for both R and S analytes. This cancellation of errors 

First those authors considered the binding site on the CSP. This is simply where the analytes spend most of their time around the CSP. The main question was do both analytes bind to the same place on the CSP or to different places A priori there is no way of knowing this, but by examining the intermolecular potential energy surfaces they were able to conclude, for the analytes studied, that the binding sites are the same for both enantiomers indicating that it is not where the analyte binds that is important but rather how it binds that is important. 

Next they considered the stereodifferentiation process itself. An energy partitioning scheme was developed allowing them to divide the total binding enthalpy into molecular fragments constituting the CSP and/or the analyte. The idea to examine intermolecular energies attributable to parts of one molecule with another came from 

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Ewing TJ, Makino S, Skillman AG, Kuntz ID. DOCK 4.0 search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Dei 2001 15 411-28. 

Ewing, T.J.A., Makino, S., Skillman, A.G., and Kuntz, I.D. (2001) DOCK4.0 search strategies for automated molecular docking of fiexible molecule databases. Journal of Computer-Aided Molecular Design, 15, 411-428. 

Such techniques mean that the chemical literature may be used more effectively, and that its use can be partially automated. Might this lead to a way of automating organic synthesis To make most molecules there are many strategies which may be successful. If each reaction of each strategy can be evaluated for similarity to a reaction recorded in the literature, it should be possible to develop a route to most molecules by mechanically searching the chemical literature, so that suitable precedent is found for every transformation. 

Weber, P. C. (1990). A protein crystallization strategy using automated grid searches on successively finer grids. 

MARKVSH TOPFRAG. Derwent s TOPFRAG family of products is PC -hased software that automates the selection of search codes and strategies. 

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