Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases

被引：12

作者：

Akaki, Tatsuo ^{[1
]}

Bessho, Yuki ^{[1
]}

Ito, Takashi ^{[1
]}

Fujioka, Shingo ^{[1
]}

Ubukata, Minoru ^{[1
]}

Mori, Genki ^{[1
]}

Yamanaka, Kenji ^{[2
]}

Orita, Takuya ^{[1
]}

Doi, Satoki ^{[1
]}

Iwanaga, Tomoko ^{[1
]}

Ikegashira, Kazutaka ^{[1
]}

Hantani, Yoshiji ^{[2
]}

Nakanishi, Isao ^{[3
]}

Adachi, Tsuyoshi ^{[1
]}

机构：

[1] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Chem Res Labs, 1-1 Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[2] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Biol Pharmacol Res Labs, 1-1 Murasaki Cho, Takatsuki, Osaka 5691125, Japan

[3] Kindai Univ, Dept Pharmaceut Sci, Computat Drug Design & Discovery, Higashiosaka, Osaka 5778502, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2021年 / 44卷

关键词：

Fragment-based drug discovery (FBDD); X-ray fragment hit; Pyruvate Dehydrogenase Kinases (PDHKs); ATP binding site; PHOSPHORYLATION; IDENTIFICATION; INTEGRATION; DOMAIN; ROLES; PDK4;

D O I：

10.1016/j.bmc.2021.116283

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.

引用

页数：15