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Visualized and quantitative structural analysis ofpeptidomimetics for PPI drug discovery
Hajime Takashima 1

Atsushi Yoshimori 2

Eiji Honda 1

takashima@prismbiolab.com

yoshimori@itmol.com

honda@prismbiolab.com

Tomonori Taguri 1

Jun Ozawa 1

Satoshi Shuto 3

taguri@prismbiolab.com

ozawa@prismbiolab.com

shu@pharm.hokudai.ac.jp

Shunji Suetaka 4
shunji-suetaka@g.ecc.u-tokyo.ac.jp

Nao Sato 4

sato-nao140@g.ecc.u-tokyo.ac.jp

Yuuki Hayashi 4

Munehito Arai 4,5

hayashi@bio.c.u-tokyo.ac.jp

arai@bio.c.u-tokyo.ac.jp

Dai Takehara 1
takehara@prismbiolab.com

1

PRISM BioLab Co., Ltd., 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa, 251-0012, Japan
Institute for Theoretical Medicine, Inc., 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa, 251-0012, Japan
3
Faculty of Pharmaceutical Science, Hokkaido University 160-8582, Kita 8, Nishi 5, Kita-ku, Sapporo,Hokkaido, 060-0808, Japan
4
Department of Life Sciences, Graduate School of Arts and Scie nces, The University of Tokyo, 3-8-1
Meguro, Komaba, Tokyo 153-8902, Japan
5
Department of Physics, Graduate School of Science, The University of Tokyo, 3-8-1 Meguro, Komaba,
Tokyo 153-8902, Japan
2Keywords: Peptidomimetics, Conformational analysis, PepMetics TM Library, PPIs
Protein–protein interactions (PPIs) are significant drug targets and many peptidomimetic
molecules have been developed for modulating PPIs [1]. Nevertheless, no analytical method has
been established to evaluate how precisely these molecules can mimic target peptide structures.
We developed new methods which enable visual, comprehensive, and quantitative analysis ofthree-dimensional structures of peptidomimetics: peptide conformation distribution (PCD) plot andpeptidomimetic analysis (PMA) map [2]. These methods are based on the conformational analysisof multiple side-chain C α -C β bonds of a peptide fragment and their corresponding bonds(pseudo-C α -C β bonds) in a peptidomimetic molecule, instead of the Ramachandran plot [3] using φand ψ angles of a single amino acid. PCD-plot is an alignment-free method and visually clarifies
conformation distribution of peptidomimetic molecules in the chemical space and similarity with
its target peptide secondary structures. PMA-map is an alignment-based method and canquantitatively evaluate similarity between various types of peptidomimetic molecules and theirtarget peptide structures.
Results obtained from analysis using these two methods indicated that our PepMetics TM scaffold,multi-facial α-helix mimetics, is an excellent peptidomimetics that can mimic spatial positioningof the side-chains of α-helix precisely. We have developed a peptidomimetic compound library(PepMetics TM Library) using our PepMetics TM scaffolds and have found PPI hit compounds for theinteractions of KIX and c-Myb/MLL proteins known as targets for cancer and leukemia.
In summary, our methods and strategies are useful for development of new peptidomimetic
molecules and rational PPI drug discovery.
[1] Milroy, L. G.; et al., Modulators of protein-protein interactions, Chem. Rev., 2014, 114, 4695-4748.
[2] Takashima, H.; Yoshimori, A.; et al., Visualized and quantitative conformational analysis ofpeptidomimetics, submitted.
[3] Ramachandran, G. N.; et al., Stereochemistry of polypeptide chain configurations, J. Mol. Biol.,
1963, 7, 95–99.