Rational grid

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

A neutral macrocyclic receptor of nitrate was designed by a rational approach. [1] A hexagonal grid was constructed around the trigonal nitrate anion and the molecular frame was cut from the chicken wire pattern (Scheme 1). 

Kim s group also prepared the l,12-diphenyl-5,8-dioxa-2,ll-dithidodecane ligand L44 and reacted it with Cul.164 Contrary to our failure to assemble a network with 1,8 bis(phenylthio)octane, L44 containing eight spacer units between the sulfur atoms allowed the construction of a 2D square-grid-type coordination polymer 44. This finding may be rationalized by the enhanced basicity of -S-benzyl vs. -S-phenyl (Scheme 23). 

An alternative grid, shown in red, defines an alternative set of planes that also contains all equivalent atoms, and under different conditions, also satisfies Bragg s equation. Such planes, which may be constructed in an endless number of ways, all have one property in common - they make rational intercepts on the axes of the unit cell. The fractional intercepts are defined as a/h, h/k, c/l in terms of the unit cell constants and the integer Miller indices, hkl. 

The close integration of MIF calculation, chemometrical analysis and visualization in GOLPE is an additional advantage which allows a straightforward application of the methodology. With GRID MIFs from different probes, one achieves a comprehensive description of possible interactions in the binding site. Additionally, PCA is a very effective tool for the comparison of the structures on a rational basis. 

Cruciani, G., Pastor, M., Clementi, S., dementi, S. GRIND (GRID independent descriptors) in 3D structure-metabolism relationships, in Rational Approaches to Drug Design, Hoitje, H.D. and SippI, W. (eds.), Prous Science Press, Barcelona, 2001, pp. 251-260. 

Moreover GRID can be used to understand the structural differences related to enzyme selectivity, a fundamental field in the rational design of drugs. GRID maps can also be used as descriptor input in statistical procedures like CoMFA, GOLPE or SIMCA for QSAR or 3D-QSAR analyses. 

Virtually all the needs of Brasilia s future residents were reflected in the plan. It is just that these needs were the same abstract, schematic needs that produced the formulas for Le Corbusier s plans. Although it was surely a rational, healthy, rather egalitarian, state-created city, its plans made not the slightest concession to the desires, history, and practices of its residents. In some important respects, Brasilia is to Sao Paulo or Rio as scientific forestry is to the unplanned forest. Both plans are highly legible, planned simplifications devised to create an efficient order that can be monitored and directed from above. Both plans, as we shall see, miscarry in comparable respects. Finally, both plans change the city and the woods to conform to the simple grid of the planner. 

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