Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors

[Display omitted] Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PD...

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Veröffentlicht in:Bioorganic & medicinal chemistry 2021-12, Vol.52, p.116514-116514, Article 116514
Hauptverfasser: Bessho, Yuki, Akaki, Tatsuo, Hara, Yoshinori, Yamakawa, Maki, Obika, Shingo, Mori, Genki, Ubukata, Minoru, Yasue, Katsutaka, Nakane, Yoshitomi, Terasako, Yasuo, Orita, Takuya, Doi, Satoki, Iwanaga, Tomoko, Fujishima, Ayumi, Adachi, Tsuyoshi, Ueno, Hiroshi, Motomura, Takahisa
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container_end_page 116514
container_issue
container_start_page 116514
container_title Bioorganic & medicinal chemistry
container_volume 52
creator Bessho, Yuki
Akaki, Tatsuo
Hara, Yoshinori
Yamakawa, Maki
Obika, Shingo
Mori, Genki
Ubukata, Minoru
Yasue, Katsutaka
Nakane, Yoshitomi
Terasako, Yasuo
Orita, Takuya
Doi, Satoki
Iwanaga, Tomoko
Fujishima, Ayumi
Adachi, Tsuyoshi
Ueno, Hiroshi
Motomura, Takahisa
description [Display omitted] Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.
doi_str_mv 10.1016/j.bmc.2021.116514
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In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34808405</pmid><doi>10.1016/j.bmc.2021.116514</doi><tpages>1</tpages></addata></record>
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subjects Adenosine Triphosphate - chemistry
Adenosine Triphosphate - pharmacology
Amides - chemistry
Amides - pharmacology
ATP binding site
Dose-Response Relationship, Drug
Drug Design
Humans
Intramolecular pi-pi interaction
Molecular Structure
Novel ATP lid conformation
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Pyruvate dehydrogenase kinases (PDHKs)
Structure-Activity Relationship
Structure-based drug design (SBDD)
title Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors
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