Design representative compounds

Further exploitation of the molecular shape feature has led more recently to the design of another series of clathrate hosts by substituting on the allene rigid backbone bulky groups 22>, Representative compounds of this new host family are 20 and 21. The allene 20 (R = t-butyl) shows an interesting clathration behaviour upon crystallization from various environments, including alicyclic and aromatic compounds, heterocycles, cyclic ketones and eyclohexaneamine 26>. 

The wheel-and-axle design as source for host-guest compounds was originally proposed by Toda and Hart in 1981 for hosts containing hydroxyl functions 481 (see Ch. 3, Sect. 2.1 of Vol. 140). The l,l,6,6-tetraphenylhexa-2,4-diyne-l,6-diol (24) provides a representative compound. It forms 1 2 crystalline inclusion complexes with a large number of small guest molecules, including a variety of ketones, amines, amides and a sulfoxide 48). 

Fig. 6. Error structure of HTS results. This figure shows how the reproducibility of activity data varies with differences in activity. The circles represent compounds designated as inactive and crosses designate active compounds. From this figure it is obvious that assay variability is closest at the cutoff between active and inactive compounds.

The parallel-group, double-blind, placebo-controlled study design represents the golden standard of acute treatment trials of depression, mania and anxiety disorders. This design is intended to limit bias, in particular selection and measurement bias. Trials based on this design are expected to provide information about the effect size of a new compound and its side-effect profile. 

The advent of more accurate and rapid tools in chemoin-formatics and virtual screening makes it possible to design and synthesize a small subset of representative compounds (focused library) of a larger library. Out of various improved methods these two diversity- or structure-based approaches are frequently exercised in the design of a focused library. Once the 3D coordinates of a protein target are determined by either X-ray crystal structures or NMR, a structure-based library design is a more productive and viable approach. 

Once a lead is found, we have to focus in our search of property space as rapidly as possible to understand structure-activity relationships and perhaps build pharmacophore maps. To do this, we need to design more compounds to explore ranges of properties centered around our lead. This explosion of compounds is a knowledge-gathering process which, when the compounds are tested, should increase the understanding of bioactivity. By application of the neighborhood principle to eliminate similar molecules, any molecules selected for synthesis will likely have several hundred or a thousand similar structures that are stored in a virtual library. These often represent an ideal starting point for lead follow-up. 

Compound selection is a core process of library design, and three main methods can be mentioned. Dissimilarity-based methods select compounds in terms of similar-ity/distance between individuals in chemical space. Clustering methods first group compounds into clusters based on similarity/distance and then choose representative compounds from different clusters. Partitioning methods first create a uniform cell space that subdivides the chemical space, then assign all virtual compounds to the relative cells according to their properties, and finally choose representative compounds from different cells. 

Figure 10.7. Conceptual design of compound (20), by use of the active site of E. aoU TS as a template. W represents a tightly bound water molecule. [Adapted from Babine and Bender (9).]...

Library design is also influenced by the purpose of the library to be synthesized. For lead generation studies a diverse set of compounds is desired, whereas for lead optimization studies, the library should represent compounds that will provide a representational structure-activity relationship (SAR) for the structural scaffold under investigation. For compounds to be used in HTS, members of the library should be chosen that will provide the maximum information content when evaluated in the screening system. 

The ROG surrogate used in the ambient surrogate - NOx experiments consisted of a simplified mixture of designed to represent the major elasses of hydrocarbons and aldehydes measured in ambient urban atmospheres, with one eompound used to represent each model speeies used in condensed lumped-molecule meehanism. The eight representative compounds used were n-butane, n-octane, ethene, propene, trans-2-butene, toluene, m-xylene, and formaldehyde. (See Carter et al., 1995b, for a diseussion of the derivation of this surrogate). 

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