Probing Protein Surfaces: QSAR Analysis with Helix Mimetics

Abstract

α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

A catalytic protein–proteomimetic complex: using aromatic oligoamide foldamers as activators of RNase S

“…The assay relies upon binding of ethidium bromide to unhydrolysed RNA 48. Using the remaining fluorescence as an approximation of activity, we used the assay to screen libraries of previously prepared aromatic oligoamide helix-mimetics (see ESI for structures; ESI Tables S1 and S2†) derived from O -alkylated,44,49,50 N -alkylated14 and hybrid scaffolds,43,51 for reactivation of the S-protein (ESI Fig. S1†).…”

Evolution in non-peptide α-helix mimetics on the road to effective protein-protein interaction modulators

“…In order to understand the rules that govern the molecular recognition between peptidomimetics and proteins, new oligoamide-based scaffold with an intercalated α-amino acid were studied on the p53-HDM2 interaction. They tried to mimic key residues of p53 (Phe19, Trp23, Leu26), and identified compound 28 (Figure 6) as a selective inhibitor of this interaction, at a micromolar QSAR analysis of this type of oligoamide-based p53/HDM2 inhibitors was also carried out [71], studying hydrophobicity, electronic and steric effects, as well as H-bonding interactions, by changing para substituents on the benzyl ring of central Phe. These studies indicated that the dominant contribution on the inhibitory activity is the hydrophobic character of the central amino acid residue, due to the hydrophobic nature of the binding site.…”

Auszeichnungen der Royal Society of Chemistry 2016

“…Sein Forschungsschwerpunkt ist der Einsatz von synthetischen Verbindungen, um molekulare Erkennung und Selbstorganisation zu verstehen und zu steuern, mit einer besonderen Betonung auf der Inhibierung von Protein‐Protein‐Wechselwirkungen. Er war gemeinsam mit Patrick T. Gunning Gastherausgeber von ChemBioChem ‐ und ChemMedChem ‐Sonderheften über Protein‐Protein‐Wechselwirkungen, und schrieb einen Beitrag über α‐Helix‐vermittelte Protein‐Protein‐Wechselwirkungen …”