Structural studies, lead compounds molecules

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

Another approach is to compare polymorphic forms of the same compound. This allows the comparison of molecules with the same constitution and configuration in different crystal fields. Do these different potential environments lead to different conformations There are few comparative crystal structural studies of organic polymorphs. For d-mannitol the molecules had the same conformation in all three polymorphic forms studied with differences in torsion angles for the two that were studied in detail of only a few degrees (see Table I). 

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

The modern tools available in synthetic chemistry, either from the organic viewpoint or concerning the preparation of transition metal complexes, allow one to prepare more and more sophisticated molecular systems. In parallel, time-resolved photochemistry and photophysics are nowadays particularly efficient to disentangle complex photochemical processes taking place on multicomponent molecules. In the present chapter, we have shown that the combination of the two types of expertise, namely synthesis and photochemistry, permits to tackle ambitious problems related to artificial photosynthesis or controlled dynamic systems. Although the two families of compounds made and studied lead to completely different properties and, potentially, to applications in very remote directions, the structural analogy of the complexes used is striking. 

Abstract Nucleic acids were one of the first biological targets explored with DCC, and research into the application has continued to yield novel and useful structures for sequence- and structure-selective recognition of oligonucleotides. This chapter reviews major developments in DNA- and RNA-targeted DCC, including methods under development for the conversion of DCC-derived lead compounds into probe molecules suitable for studies in vitro and in vivo. Innovative applications of DCC for the discovery of new materials based on nucleic acids and new methods for the modification of nucleic acid structure and function are also discussed. 

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