Visualized and Quantitative Conformational Analysis of Peptidomimetics

Abstract

Protein−protein interactions (PPIs) are fundamentally important and challenging drug targets. Peptidomimetic molecules of various types have been developed to modulate PPIs. A particularly promising drug discovery strategy, structural peptidomimetics, was designed based on special mimicking of sidechain C α −C β bonds. It is simple and versatile. Nevertheless, no quantitative method has been established to evaluate its similarity to a target peptide motif. We developed two methods that enable visual, comprehensive, and quantitative analysis of peptidomimetics: peptide conformation distribution (PCD) plot and peptidomimetic analysis (PMA) map. These methods specifically examine multiple side-chain C α −C β bonds of a peptide fragment motif and their corresponding bonds (pseudo-C α −C β bonds) in a mimetic molecule instead of φ and ψ angles of a single amino acid in the traditional Ramachandran plot. The PCD plot is an alignment-free method, whereas the PMA map is an alignment-based method providing distinctive and complementary analysis. Results obtained from analysis using these two methods indicate our multifacial α-helix mimetic scaffold 12 as an excellent peptidomimetic that can precisely mimic the spatial positioning of side-chain functional groups of α-helix. These methods are useful for visualized and quantified evaluation of peptidomimetics and for the rational design of new mimetic scaffolds.

Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1

“…PepMetics ® is quite useful as a small-molecule scaffold to mimic β-turn and α-helix. Our earlier report explained its superiority to other peptide-mimicking scaffolds by peptide conformation distribution-plot (PCD-plot) analysis [14], and the findings of this study indicate that it is useful as a β-turn-mimicking scaffold (Figure 6B,C). If compounds that mimic all patterns of the three consecutive amino acid sequence of the cyclic peptide are synthesized sequentially from the end (Figure 6D), then one of them will bind to the site on the target protein where the cyclic peptide binds.…”

Strategies for converting turn-motif and cyclic peptides to small molecules for targeting protein–protein interactions

“… 25 Alanine scan mutagenesis highlighted eight mutants (H2, P3, L5, P6, I7, S9, H11, and F12) led to a decrease in binding with CTLA-4. In the absence of structural data, the team computationally modelled consecutive trimers of amino acid side chains onto 40 virtual scaffolds, highlighted previously by Takashima et al in their development of “Pepmetics”, 26 and performed molecular docking of these compounds to CTLA-4. Tsuihiji et al proposed that three consecutive residues imprinted on a small molecule skeleton would emulate a β-turn, a common binding motif in cyclic peptides, and hypothesised to be responsible for the binding of 1.…”