1,721,028 research outputs found
Amphiphilic a-helix mimetics based on a benzoylurea scaffold
No full textThe design and synthesis of amphiphilic benzoylurea ?-helix mimetics is described. These conformationally constrained molecules allow for the correct angular and spatial projection of hydrophobic and hydrophilic groups and thus the reproduction of side-chains on both faces of an ?-helix
An alpha-helical peptidomimetic scaffold for dynamic combinatorial library formation
No full textA novel oligobenzamide-based alpha-helix mimetic was designed and synthesised with either imine or hydrazone functionalities that serve both to pre-organise the side-chain vectors to mimic the i, i + 4 and i + 7 residues of an alpha-helix, and to allow for the facile creation of dynamic libraries
Conformational control by intramolecular hydrogen bonding
Full text linkHydrogen bonds are directional, non-covalent interactions between hydrogen and electronegative atoms. Although generally weak, these interactions are critical to the stability of many biological systems including proteins and DNA. This dissertation explores small molecules in which an intramolecular hydrogen bond is the key determinant of conformation. Chapter 1 introduces the protein Grb2 SH3C, details its role in cancer signalling, and delineates the idea of peptidomimetics—small molecules which are functionalized to mimic the structure of a peptide and disrupt protein-protein interactions. Chapter 2 describes a virtual screen for binders to Grb2 SH3C. From a library of 6.3 million compounds, 34 were tested in vitro and two found to bind to the protein in two orthogonal assays. Chapter 3 describes mimics of the polyproline II helix using a benzoylurea scaffold. A small library of these compounds was synthesized and tested for binding to Grb2 SH3C using SPR, a competition assay, and NMR. Chapter 4 describes attempts to mimic a 310 helix using benzamide-based peptidomimetics. The synthesis and in vitro evaluation of these molecules as ligands of Grb2 SH3C is described. Chapter 5 uses quantum chemical calculations to assess the energies of a series of molecular switches. These calculations benchmark a range of modern density functional theory calculations, and attempt to quantify the accuracy of these methods for a large, flexible system. The role of solvation, entropy, geometry, and torsional angles are assessed in accurately calculating the energies of the critical hydrogen bonds
a-helix mimetics: outwards and upwards
No full text?-Helices are common secondary structural elements forming key parts of the large, generally featureless interfacial regions of many therapeutically-relevant protein–protein interactions (PPIs). The rational design of helix mimetics is an appealing small-molecule strategy for the mediation of aberrant PPIs, however the first generation of scaffolds presented a relatively small number of residues on a single recognition surface. Increasingly, helices involved in PPIs are found to have more complex binding modes, utilizing two or three recognition surfaces, or binding with extended points of contact. To address these unmet needs the design and synthesis of new generations of multi-sided, extended, and supersecondary structures are underway
Unpicking the determinants of amide NH••O=C hydrogen bond strength with diphenylacetylene molecular balances
No full textHydrogen bonding plays an essential part in dictating the properties of natural and synthetic materials. Secondary amides are well suited to cross–strand interactions through the display of both hydrogen bond donors and acceptors and are prevalent in polymers such as proteins, nylon, and Kevlar(TM). In attempting to measure hydrogen bond strength and to delineate the stereoelectronic components of the interaction, context frequently becomes vitally important. This makes molecular balances – systems in which direct comparison of two groups is possible – an appealing bottom up approach that allows the complexity of larger systems to be stripped away. We have previously reported a family of single molecule conformational switches that are responsive to diverse stimuli including Brønsted and Lewis acids, anions, and redox gradients. In this work we assess the ability of the scaffold, based on a 2,6-disubstituted diphenylacetylene, to measure accurately the difference in hydrogen bond strength between variously functionalised amides. In all of the examples investigated hydrogen bond strength closely correlate to measures of Brønstead acidity suggesting that the scaffold is well-suited as a platform for the accurate determination of bond strength in variously substituted systems
Super-secondary structure peptidomimetics: design and synthesis of an a–a hairpin analogue
No full textThe ?–? helix motif presents key recognition domains in protein–protein and protein–oligonucleotide binding, and is one of the most common super-secondary structures. Herein, we describe the design, synthesis and structural characterisation of an ?–? hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two ?-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side chains of the i and i+4 residues of two helices
Non-covalent S⋯O interactions control conformation in a scaffold that disrupts islet amyloid polypeptide fibrillation
Full text linkConformationally-constrained molecules that selectively recognise the surfaces of proteins have the potential to direct the path of protein folding. Such molecules are of therapeutic interest because the misfolding of proteins, especially that which results in fibrillation and aggregation, is strongly correlated with numerous diseases. Here we report the novel use of S⋯O interactions as a conformational control element in a new class of non-peptidic scaffold that mimics key elements of protein surfaces. These molecules disrupt the fibrillation of islet amyloid polypeptide (IAPP), a process that is implicated in the pathology of type II diabetes
Acid-mediated topological control in a functionalized foldamer
No full textInduced conformational change provides a powerful mechanism to modulate the structure and function of molecules. Here we describe the synthesis of chiral, surface-functionalized oligomeric pyridine/imidazolidin-2-one foldamers, and interrogate their acid-mediated transition between linear and helical topologies
Ion-mediated conformational switches
No full textMolecular switches are ubiquitous in Nature and provide the basis of many forms of transport and signalling. Single synthetic molecules that change conformation, and thus function, reversibly in a stimulus-dependent manner are of great interest not only to chemists but society in general; myriad applications exist in storage, display, sensing and medicine. Here we describe recent developments in the area of ion-mediated switching
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