A Novel Rigid β-Turn Molecular Scaffold

Lombardi, Angela; D’Auria, Gabriella; Maglio, Ornella; Nastri, Flavia; Quartara, Laura; Pedone, and Carlo; Pavone, Vincenzo

doi:10.1021/ja9643329

Cited by 16 publications

(14 citation statements)

References 65 publications

(130 reference statements)

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“…In many cases, such conformational changes are accompanied by alterations in the bioactivity profiles of the resulting analogue (1). As an example of these, there have been numerous efforts to develop analogues that stabilize the β‐turn conformation (2–6) because of its structural and biological importance (7–10); β‐turns are found in all proteins and occur on the exposed surface or between two antiparallel β‐strands of proteins, they act as key a recognition element in the initiation of biological events. β‐Turns are determined by four consecutive residues (denoted i , i + 1, i + 2 and i + 3) and these turns are differentiated by the backbone conformations of residues i + 1 and i + 2, represented by the torsion angles φ i +1 , ψ i +1 , φ i +2 and ψ i +2 (11).…”

Section: Standard Backbone Angles For the Major Types Of β‐Turnmentioning

confidence: 99%

Role of azaamino acid residue in β‐turn formation and stability in designed peptide

Lee

Ahn

et al. 2000

The Journal of Peptide Research

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The structural perturbation induced by C(alpha)-->N(alpha) exchange in azaamino acid-containing peptides was predicted by ab initio calculation of the 6-31G* and 3-21G* levels. The global energy-minimum conformations for model compounds, For-azaXaa-NH2 (Xaa=Gly, Ala, Leu) appeared to be the beta-turn motif with a dihedral angle of phi= +/- 90 degrees, psi=0 degrees. This suggests that incorporation of the azaXaa residue into the i+2 position of designed peptides could stabilize the beta-turn structure. The model azaLeu-containing peptide, Boc-Phe-azaLeu-Ala-OMe, which is predicted to adopt a beta-turn conformation was designed and synthesized in order to experimentally elucidate the role of the azaamino acid residue. Its structural preference in organic solvents was investigated using 1H NMR, molecular modelling and IR spectroscopy. The temperature coefficients of amide protons, the characteristic NOE patterns, the restrained molecular dynamics simulation and IR spectroscopy defined the dihedral angles [ (phi i+1, psi i+1) (phi i+2, psi i+2)] of the Phe-azaLeu fragment in the model peptide, Boc-Phe-azaLeu-Ala-OMe, as [(-59 degrees, 127 degrees) (107 degrees, -4 degrees)]. This solution conformation supports a betaII-turn structural preference in azaLeu-containing peptides as predicted by the quantum chemical calculation. Therefore, intercalation of the azaamino acid residue into the i+2 position in synthetic peptides is expected to provide a stable beta-turn formation, and this could be utilized in the design of new peptidomimetics adopting a beta-turn scaffold.

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Section: Standard Backbone Angles For the Major Types Of β‐Turnmentioning

confidence: 99%

Role of azaamino acid residue in β‐turn formation and stability in designed peptide

Lee

Ahn

et al. 2000

The Journal of Peptide Research

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“…b-turns are an important recognition element of peptides and proteins, and a great deal of scientific effort has been applied to classifying, designing and synthesizing b-turn mimetics [15,[33][34][35][36][37][38][39][40][41][42][43]. However, the traditional classification of b-turns is based on backbone criterion, which has little reflection on the position of the important recognition elements, the side chains.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the importance of side chain spatial arrangements in molecular recognition, b-turns are currently classified into nine types based on the main chain dihedral angles, /2, w2, /3 and w3 [2,[29][30][31][32]. Although this classification of b-turns has been extremely useful and has been used widely to design peptidomimetics [15,[33][34][35][36][37][38][39][40][41][42][43], it makes very little functional sense, as it is not side-chain based. In addition, and as we will illustrate, each type of b-turn in the current classification can have two or more clusters of side chain spatial arrangements and different types of ''classical'' b-turns can have the same side chain spatial arrangement.…”

mentioning

confidence: 99%

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

Tran¹,

McKie

Meutermans

et al. 2005

J Comput Aided Mol Des

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Beta-turns are important topological motifs for biological recognition of proteins and peptides. Organic molecules that sample the side chain positions of beta-turns have shown broad binding capacity to multiple different receptors, for example benzodiazepines. Beta-turns have traditionally been classified into various types based on the backbone dihedral angles (phi2, psi2, phi3 and psi3). Indeed, 57-68% of beta-turns are currently classified into 8 different backbone families (Type I, Type II, Type I', Type II', Type VIII, Type VIa1, Type VIa2 and Type VIb and Type IV which represents unclassified beta-turns). Although this classification of beta-turns has been useful, the resulting beta-turn types are not ideal for the design of beta-turn mimetics as they do not reflect topological features of the recognition elements, the side chains. To overcome this, we have extracted beta-turns from a data set of non-homologous and high-resolution protein crystal structures. The side chain positions, as defined by C(alpha)-C(beta) vectors, of these turns have been clustered using the kth nearest neighbor clustering and filtered nearest centroid sorting algorithms. Nine clusters were obtained that cluster 90% of the data, and the average intra-cluster RMSD of the four C(alpha)-C(beta) vectors is 0.36. The nine clusters therefore represent the topology of the side chain scaffold architecture of the vast majority of beta-turns. The mean structures of the nine clusters are useful for the development of beta-turn mimetics and as biological descriptors for focusing combinatorial chemistry towards biologically relevant topological space.

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“…A great deal of scientific effort has been applied to classify, design and synthesize b-turn mimetics [47,[55][56][57][58][59][60][61][62][63][64][65][66][67][68]. To compare our clustering of loops with the traditional b-turn type classification as defined by Hutchinson and Thornton [69], the loops in the vector plots in Fig.…”

Section: Relationship Between the 39 Clustersmentioning

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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A Novel Rigid β-Turn Molecular Scaffold

Cited by 16 publications

References 65 publications

Role of azaamino acid residue in β‐turn formation and stability in designed peptide

Role of azaamino acid residue in β‐turn formation and stability in designed peptide

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

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

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