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“Reversible molecular interactions are at the heart of the dance of life.” Lubert Stryer
Biochemical systems, their communication pathways, and the related transformations that take place are based on molecular interactions, so we may safely say that these regulate life at a molecular level. For basic science studies or for therapeutic purposes, we can perturb these systems with chemical manipulations. Because of the accumulated knowledge in the fields of organic chemistry and molecular recognition, our investigative instruments have become increasingly powerful. During the last fifty years, there has been a continuous evolution in chemical approaches to interact with biological systems, and fragment-based drug discovery can be considered one of the products of this evolution . In short, fragment-based ligand discovery (FBLD) may be described as the search for a ligand for a macromolecule, which may constitute a lead for a medicinal chemistry program, through the use of very small molecules. This approach, as we will see, may provide a number of advantages over the classical approaches together with the logical consequence that the observed affinities for a good lead compound will fall in the micromolar-millimolar range rather than in the nanomolar range, necessitating that chemists and biologists leave behind the high-affinity paradigm.
This chapter discusses in detail the historical background, key concepts, and basis for the FBLD approach. An illustration of the technology involved will follow, together with a selection of practical and successful applications.
The anatomy of Xanthomaculna convolute shows adaptation to a vagrant life form and to the moisture conditions of its habitat. The differential swelling of the irregularly thickened upper cortex and the medulla, in addition to the rigid medullary structure, due to the deposition of calcium oxalate, allow orderly hygroscopic thalline movements. The architecture of the medulla appears to be closely related to masonry-like arches where the material is only stressed by compression and the stresses are distributed at the hinges. The possible role of crystalline medullary deposition as a radiation reflector is also suggested.
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