In Silico Design, Synthesis, and Evaluation of PROTAC Against Hematopoietic Prostaglandin D Synthase

Hidetomo Yokoo; Norihito Shibata; Yosuke Demizu

doi:10.1007/978-1-0716-3985-6_18

In Silico Design, Synthesis, and Evaluation of PROTAC Against Hematopoietic Prostaglandin D Synthase

Methods Mol Biol. 2024:2780:345-359. doi: 10.1007/978-1-0716-3985-6_18.

Authors

Hidetomo Yokoo^{1

2}, Norihito Shibata³, Yosuke Demizu^{4

5

6}

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
² Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto, Japan.
³ Division of Biochemistry, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan. [email protected].
⁴ Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan. [email protected].
⁵ Graduate School of Medical Life Science, Yokohama City University, Yokohama-shi, Kanagawa, Japan. [email protected].
⁶ Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan. [email protected].

PMID: 38987477
DOI: 10.1007/978-1-0716-3985-6_18

Abstract

Chemical protein knockdown technology using proteolysis-targeting chimeras (PROTACs) to hijack the endogenous ubiquitin-proteasome system is a powerful strategy to degrade disease-related proteins. This chapter describes in silico design of a hematopoietic prostaglandin D synthase (H-PGDS) degrader, PROTAC(H-PGDS), using a docking simulation of the ternary complex of H-PGDS/PROTAC/E3 ligase as well as the synthesis of the designed PROTAC(H-PGDS)s and evaluation of their H-PGDS degradation activity.

Keywords: Hematopoietic prostaglandin D synthase; In silico molecular design; PROTAC; Protein knockdown; Ubiquitin-proteasome system.

MeSH terms

Computer Simulation
Drug Design
Humans
Intramolecular Oxidoreductases* / antagonists & inhibitors
Intramolecular Oxidoreductases* / chemistry
Intramolecular Oxidoreductases* / metabolism
Lipocalins* / chemistry
Lipocalins* / metabolism
Molecular Docking Simulation*
Proteasome Endopeptidase Complex / chemistry
Proteasome Endopeptidase Complex / metabolism
Proteolysis*
Ubiquitin-Protein Ligases / metabolism

Substances

prostaglandin R2 D-isomerase
Intramolecular Oxidoreductases
Lipocalins
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex