Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.
The use of a "Field Mapping" beam shaping technique for generating near field Gaussian intensity patterns from uniform intensity ("flat top") laser beams is described. The design objective was to simulate realistic High Energy Laser (HEL) far field intensity patterns for laser effects testing purposes, without having to propagate the large distances necessary to obtain the true far field intensity profile and beam size typical of realistic target engagement scenarios.The field mapping approach presented uses a continuous surface mirror with a figure designed to redistribute the energy into a Gaussian distribution at the target plane. The use of a reflective system was desired to minimize cost and maximize wavelength diversity and laser damage threshold capability. Physical optics analyses are presented to illustrate the performance characteristics of a totally passive reflective field mapping beam shaper.
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