Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations

Hruby, Victor J.; Al‐Obeidi, Fahad; Kazmierski, Wieslaw M.

doi:10.1042/bj2680249

Cited by 521 publications

(373 citation statements)

References 70 publications

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“…The synthetic methods did not give all possible conformations, due to the lack of a robust methodology for varying the size and stereochemistry of the mimetics. Here we report a novel parallel synthetic strategy for [6,5]-and [7,5]-thiazolidinone bicyclo [2,3] -Leu-enkephalin analogues with different geometries using unconventional solid-phase synthesis ( Figure 1). In our synthesis, the ␤-side chains (R iϩ1 and R iϩ2 ) are not considered in amino acid precursors 4 and 5 because positions 2-3 in Leu-enkephalin are Gly-Gly.…”

Section: Figurementioning

confidence: 99%

“…Bicyclic dipeptide mimetics have been designed and synthesized in this area for over ten years. 9,10 Previous studies have found that a [5,5]-bicyclic mimetic could approximate a type II ␤-turn, 11,12 a [6,5]-bicyclic could closely mimic a type IIЈ ␤-turn, 12,13 while a [7,5]-bicyclic structure can lead to different reverse turn structures depending on the chirality. 14 However, introduction of these bicyclic scaffolds into peptides has been quite limited because multistep syntheses were required, but were difficult to accomplish.…”

Section: Introductionmentioning

confidence: 99%

“…Cysteine derivatives 5 with S ␤ -Fm protection has been chosen so that the deprotection of the N ␣ -Fmoc (9-fluorenylmethoxycarbonyl) and the S ␤ -Fm can be performed simultaneously. In a previous article, we recently demonstrated that [5,5]-bicyclic dipeptides can be generated on solid-phase supports. 15 Four bicyclo [2,3] -Leu-enkephalin analogues were prepared in parallel synthesis and their biological activities evaluated.…”

Section: Introductionmentioning

confidence: 99%

“…15 Four bicyclo [2,3] -Leu-enkephalin analogues were prepared in parallel synthesis and their biological activities evaluated. Unfortunately, this simple and efficient methodology cannot be directly applied to [6,5]-and [7,5]-bicyclic dipeptide synthesis due to the formation of a 5-and 6-membered hemiaminal. 16,17 A novel methodology has to be developed here so that the synthesis can be performed on the solid-phase support.…”

Section: Introductionmentioning

confidence: 99%

“…

Abstract: Parallel synthesis of peptides and peptidomimetics has been an important approach to [6,[5][6][7]

…”

mentioning

confidence: 99%

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…

Abstract: Parallel synthesis of peptides and peptidomimetics has been an important approach to [6,[5][6][7]

…”

mentioning

confidence: 99%

See 3 more Smart Citations

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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Identification of a decapeptide with the binding reactivity for tumor-associated TAG72 antigen from a phage displayed library

Gui¹,

Moyana²,

Malcolm³

et al. 1996

Proteins

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Screening a peptidyl database for potential ligands to proteins with side-chain flexibility

et al. 1998

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The three key challenges addressed in our development of SPECITOPE, a tool for screening large structural databases for potential ligands to a protein, are to eliminate infeasible candidates early in the search, incorporate ligand and protein side-chain flexibility upon docking, and provide an appropriate rank for potential new ligands. The protein ligand-binding site is modeled by a shell of surface atoms and by hydrogen-bonding template points for the ligand to match, conferring specificity to the interaction. SPECITOPE combinatorially matches all hydrogen-bond donors and acceptors of the screened molecules to the template points. By eliminating molecules that cannot match distance or hydrogen-bond constraints, the transformation of potential docking candidates into the ligand-binding site and the shape and hydrophobic complementarity evaluations are only required for a small subset of the database. SPECITOPE screens 140,000 peptide fragments in about an hour and has identified and docked known inhibitors and potential new ligands to the free structures of four distinct targets: a serine protease, a DNA repair enzyme, an aspartic proteinase, and a glycosyltransferase. For all four, protein side-chain rotations were critical for successful docking, emphasizing the importance of inducible complementarity for accurately modeling ligand interactions. SPECITOPE has a range of potential applications for understanding and engineering protein recognition, from inhibitor and linker design to protein docking and macromolecular assembly.

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Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations

Cited by 521 publications

References 70 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Identification of a decapeptide with the binding reactivity for tumor-associated TAG72 antigen from a phage displayed library

Screening a peptidyl database for potential ligands to proteins with side-chain flexibility

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Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations

Cited by 521 publications

References 70 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Identification of a decapeptide with the binding reactivity for tumor-associated TAG72 antigen from a phage displayed library

Screening a peptidyl database for potential ligands to proteins with side-chain flexibility

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Product

Resources

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues