Fragments optimization

Fig. 1.13 Adenosine kinase inhibitor designed using fragment optimization approach.

Systematic variation is also useful for optimizing certain properties (e.g., solubility, novelty, toxicity, or metabolic stability) of a lead molecule. The fragment optimization... 

Virtual combinatorial compound libraries can be constructed and docked against the target [40 2]. This latter approach is likely to be more suitable for the fragment-optimization phase of a project, when the virtual library can be constructed around an initial fragment hit, with varying substitution patterns on pre-defined attachment points. The compounds can then be docked either in an imrestrained fashion, or, more usefully, using the 3D structure of the initial hit as a constraint or restraint [35]. 

Vangrevelinghe, E., and Rudisser, S. (2007). Computational approaches for fragment optimization. Current Computer-Aided Drug Design 3, 69-83. 

Figure 12.31. The fragment optimization ap-proacfi developed from SAE. by NMR. A known ligand of a protein is broken into fragments and small molecules based on the fragments are screened for binding. Any molecules that are found to bind can then be incorporated into the original lead compound with the hope of improving its binding and/or physicochemical properties.

Dissecting the Energetics of Fragment Binding and Fragment Optimization... 

X-ray crystallography provides detailed structural information of the bound pose of a fragment. This benefit is so significant that some practitioners in the field do not embark on fragment optimization without crystallographic structural information, and several pharmaceutical companies were created on the... 

Synthesis of Natural and Nonnatural Heparin Fragments Optimizations and Applications toward Modulation of FGF2-Mediated FGFR Signaling... 

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