Systematic structural variation

The main factor in determining the handedness of the cholesterics induced by bridged 1,1 -binaphtliyls is the helicity (P or M) of the solute, and this observation is the basis of many configurational studies of chiral binaphthyls. All the homochiral (aP)-binaphthyls 15-19 have an M helicity of the core, and all induce, in biphenyl nematics, M cholesterics.65,75 By systematic structural variations of the covalent bridge, it is possible to obtain I J -binaphthalenes with dihedral angles ranging from 60° to 96° (see series 20-24) the handedness of the cholesteric phase always matches the helicity... 

Fig. 5.17 Systematic structural variation to form membrane piercing compounds [60]...

The systematic structural variation needed for drug discovery studies will often be impossible without mastery of complex chemistry... 

Figure 9-11 Application of SAR-by-NMR to the development of a metalloprotease inhibitor. Screening of a library of small organic compounds revealed acetohydroxamic acid and 4-phenylpyrimidine as weakly binding to stromelysin (Kd 17 mM and 20 mM, respectively) at adjacent sites left, the contour lines symbolize the protein surface). After introduction of an appropriate linker (shown in grey, right panel) and systematic structural variations, a highly potent inhibitor of stromelysin and gelatinase A (IC50 = 25 nM, right) could be developed within a few months. [37], [38].

Systematic structural variation 1040 Mechanisms in biological chemistry 1149... 

All PE have a hydrophobic chain in their structure, which makes the total absence of hydrophobic interactions in PE-P complexes difficult to deny. The strongest evidence for hydrophobic interactions arises from the effects of systematic structural variations, or from thermodynamic data that exhibit the temperature dependence of the entropy and enthalpy associated to the PE-P formation [5]. The predominance of electrostatic interactions is widely accepted but there are several points of discussion about the presence of other type of intermolecular forces that participate in the PE interaction with a protein, as following ... 

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