Use in Ligand Design

The FEP method has shown good accuracy when used to determine the relative binding affinity for two structurally-related ligands. Unfortunately, the newly designed analogues requested by medicinal chemists frequently represent large structural changes from the lead compound and therefore are not well suited for the FEP method. 

Tembe and J. A. McCammon, Ligand-receptor interactions, Comput. Chem. 8 281 

Langridge, P. A. Kollman, Calculation of the relative change in binding free energy of a protein-inhibitor complex, Science 235 574 (1987). 

Erion and M. R. Reddy, Calculation of relative hydration free energy differences 

Hansen and P.A. Kollman, Free energy perturbation calculations on models of active sites Applications to adenosine deaminase inhibitors, J. Comp. Chem. 11 994 (1990). 

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Williams PA, Cosme JM, Matak-Vinkovic D, Williams MG, Jhoti H. Crystals and three-dimensional structures of human cytochrome P 450 2C9 and their use in ligand design and homology modeling. Ed. (Astex Technology Ltd. U. 2003-426058[2004053383], 806. 20040318. US. 30-4-2003. 

To produce 100 000 tonnes of nonanal per year (25% down time, 100% conversion of substrate, 80% selectivity to nonanal) requires a production rate from the reactors of 19 tonne h 1, so that each batch must be 6.3 tonnes. Assuming a 1 1 ratio by volume of fluorous solventdiquid substrate and a 75 % loading, each reactor must have a volume of 20 m3. If the distillation column were fully integrated into the system it would be required to handle 19 tonnes aldehyde h 1. An increase in selectivity to the linear product, which could be achieved using careful ligand design would reduce the reactor size by up to 25%. 

These routines should prove extremely useful in the design of high-affinity ligands for structurally characterized receptors. 

The past several years have witnessed an explosion of creativity in ligand design and asymmetric synthetic organic chemistry used in ligand preparation. This has fueled the development of new catalysts, ligands, and asymmetric transformations that should further increase the number of asymmetric hydrogenation processes at industrial scale in the years to come. 

Linear and non-linear correlations of structural parameters and strain energies with various molecular properties have been used for the design of new compounds with specific properties and for the interpretation of structures, spectra and stabilities 661. Quantitative structure-activity relationships (QSAR) have been used in drug design for over 30 years 2881 and extensions that include information on electronic features as a third dimension (the electron topological approach, ET) have been developed and tested 481 (see Section 2.3.5). Correlations that are used in the areas of electron transfer, ligand field properties, IR, NMR and EPR spectroscopy are discussed in various other Chapters. Here, we will concentrate on quantitative structure-property relationships (QSPR) that involve complex stabilities 124 289-2911. 

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