Privileged scaffolds targeting reverse-turn and helix recognition

Washington University, Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, St. Louis, MO 63110, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 02/2008; 12(1):101-14. DOI: 10.1517/14728222.12.1.101
Source: PubMed


Protein-protein interactions dominate molecular recognition in biologic systems. One major challenge for drug discovery arises from the very large surfaces that are characteristic of many protein-protein interactions.
To identify 'drug-like' small molecule leads capable of modulating protein-protein interactions based on common protein-recognition motifs, such as alpha-helices, beta-strands, reverse-turns and polyproline motifs for example.
Many proteins/peptides are unstructured under physiologic conditions and only fold into ordered structures on binding to their cellular targets. Therefore, preorganization of an inhibitor into its protein-bound conformation reduces the entropy of binding and enhances the relative affinity of the inhibitor. Accordingly, this review describes a general strategy to address the challenge based on the 'privileged structure hypothesis' [Che, PhD thesis, Washington University, 2003] that chemical templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as small-molecule inhibitors of protein-protein interactions. The authors highlight recent advances in the design of privileged scaffolds targeting reverse-turn and helical recognition.
Privileged scaffolds targeting common protein-recognition motifs are useful to help elucidate the receptor-bound conformation and to provide non-peptidic, bioavailable substructures suitable for optimization to modulate protein-protein interactions.

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Available from: Ye Che, Jan 02, 2015
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    • "Although this theory cannot be treated as a rule any longer and many exceptions can be listed, nevertheless it has become the foundation of molecular design and the concept of pharmacophores. In 2000, the concept of privileged motifs, which were formerly known as molecular moieties, which are able to construct effective ligands for diverse receptors, was further developed [64] [65] [66] [67] [68] [69] [70] [71]. The last decade has made this idea more popular and numerous moieties have been claimed to be privileged: benzazepinone [65], diphenylmethane, piperidine, biphenyltetrazole [65], indole [65] [72], biphenyl [65] [73], spiroindoline sulfonamide [65] [74], spiroindanyl piperidine [74], dihydropyridine [75], and benzopyran [76] [77]. "
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    • "Later this definition was updated by Patchett and Nargund [3]. Since then, several reviews deal with the concept of privileged motifs [4] [5] [6] [7] [8] [9] and numerous molecular fragments have been described as privileged, e.g. benzazepinone [3], diphenylmethane [3], benzylpiperidine [3], biphenyltetrazole [3], indole [3] [10], biphenyl [3] [11], spiroindoline sulfonamide [3] [12], spiroindanyl piperidine [12], 1,4-dihydropyridine [13], 2,6-dichloro- 9-thiabicyclo[3.3.1]nonane "
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