Ligand-based design

Advanced assay technology Structure-based design Ligand-based design QSAR... 

Key words Fragment-based drug design, Ligand-based NMR, Hit identification, STD, STDD, NMR-based functional assay... 

Distinguishing Molecules of Different Biol< ical Activities and Finding a New Lead Structure - An Example of Ligand-Based Drug Design... 

In this chapter, we briefly review various aspects of the chemical information systems used by the chemist for literature and patent searches the field of computer-aided drug design technologies, cheminformatics, as well as other applications. We place special emphases on the ligand-based techniques and only briefly mention the structure-based design technologies. 

Schneider G, Nettekoven M. Ligand-based combinatorial design of selective purinergic receptor (A2A) antagonists using self-organizing maps. J Comb Chem 2003 5 233-7. 

Recently, a new bidentate hemispherical chelating bisphosphite ligand based on a calixarene backbone has been designed for linear selective hydroformylation of alkenes (Scheme 9) [54], Excellent levels of regioselectivity have been observed, and even the intrinsic branched-selective hydroformylation of styrene could be overruled by this system. However, the system suffers from low catalytic activity. 

All the aforementioned protein members of the cannabinoid system are large, membrane-bound proteins therefore, it is particularly difficult to obtain direct information about their tertiary structure. Thus, at the present time, structure-based drug design is not feasible. Detailed exploration of the SAR and subsequent ligand-based design are the most appropriate means for the development of molecular probes for these proteins. 

This example is one where the accurate three-dimensional structure of the protein is unknown under these circumstances, it is necessary to create a computer model. The development of inhibitors that are designed to overcome the effects of this mutation could not be based on the accurate structure of a ligand-binding site here, ligand-based design would be appropriate (see Sect. 7.9). 

In the absence of useful three-dimensional information about the site, the designer can only build novel molecular structures based on molecular similarity with existing active molecules. Ligand-based design requires the resolution of a number of technical issues. These are itemized below. 

As a result of their low redox potentials [173], bis(phthalocyaninato) lanthanide complexes are often inadvertently reduced or oxidized, and they are also very sensitive to acids and bases. In order to solve these problems, Veciana et al. achieved certain success on designing a series of novel compounds with characteristics that would give them improved redox stability. Electroactive ligands based on phthalo-cyaninato tetra dicarboximide [175] or perfluorinated phthalocyanine [176] were used to assemble the double-decker lanthanide complexes, with the effect of stabilizing the negative charge of the anionic state of the compounds, which resulted in a strong shift of 0.7 V of their first oxidation potentials. 

A specific goal we have in mind is to design cyclophane-based a-diimine ligands for overcoming the low thermal stability of the regular a-diimine catalyst systems. 

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