Conformationally constrained nonpeptide β-turn mimetics of enkephalin

Gardner, Benjamin; Nakanishi, Hiroshi; Kahn, Michaël

doi:10.1016/s0040-4020(01)90205-4

Cited by 98 publications

(30 citation statements)

References 31 publications

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“…128 β-Lactam 147 , an ( S )-Tyr-Gly-Gly mimic synthon, was prepared from (3 S ,4 S )-1-TBS-3-but-3-enyl-4-(4-TBSO-benzyl)-β-lactam, which was obtained through highly stereoselective alkylation of (4 S )-1-TBS-4-(4-TBSO-benzyl)-β-lactam, via NaIO 4 oxidation and peptide coupling with a glycinate. ( S )-Tyr-(S)-Leu-OMe hydrazide 148 was prepared by coupling Leu-OMe with ( S )-BocNHNH-Tyr-OH, which was derived from ( R )-Tyr and BocNHNH 2 via diazonium species.…”

Section: Applications Of β-Lactam Synthon Methods For the Synthesismentioning

confidence: 99%

Advances in the chemistry of ?-lactam and its medicinal applications

2012

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Section: Applications Of β-Lactam Synthon Methods For the Synthesismentioning

confidence: 99%

Advances in the chemistry of ?-lactam and its medicinal applications

2012

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“…b-turn mimetic scaffold 18 [30,50] has an average RMSD match with the loops of 0.38 (Table 2). However, no conclusion can be drawn regarding the hypothesis because there is no reported synthesis and consequently no biological activity in SciFinder (Horizontal lined yellow in Fig.…”

Section: Biologically Relevant Descriptorsmentioning

confidence: 99%

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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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.

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“…To synthesize the third generation of compounds containing the extra methyl group within the peptide macrocycle, perform the same conformational analysis as mentioned above, and submit all prospective candidates for biological assays (months [13][14][15][16][17][18][19][20][21][22][23][24].…”

Section: Taskmentioning

confidence: 99%

“…This system was later modified by inserting alkyl or alkenyl amines in place of X with the hope of developing enkephalin mimics (Fig. (4b)) [16].…”

Section: Introduction and Overviewmentioning

confidence: 99%