Medicine Design, Pfizer Inc, Groton, Connecticut, USA.
Medicine Design, Pfizer Inc, Cambridge, Massachusetts, USA.
J Biol Chem. 2023 Mar;299(3):102959. doi: 10.1016/j.jbc.2023.102959. Epub 2023 Jan 28.
The mammalian mitochondrial branched-chain ketoacid dehydrogenase (BCKD) complex is a multienzyme complex involved in the catabolism of branched-chain amino acids. BCKD is regulated by the BCKD kinase, or BCKDK, which binds to the E2 subunit of BCKD, phosphorylates its E1 subunit, and inhibits enzymatic activity. Inhibition of the BCKD complex results in increased levels of branched-chain amino acids and branched-chain ketoacids, and this buildup has been associated with heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. To find BCKDK inhibitors for potential treatment of these diseases, we performed both NMR and virtual fragment screening and identified tetrazole-bearing fragments that bind BCKDK at multiple sites. Through structure-based virtual screening expanding from these fragments, the angiotensin receptor blocker class antihypertension drugs and angiotensin receptor blocker-like compounds were discovered to be potent BCKDK inhibitors, suggesting potential new avenues for heart failure treatment combining BCKDK inhibition and antihypertension.
哺乳动物线粒体支链酮酸脱氢酶（BCKD）复合物是一种参与支链氨基酸分解代谢的多酶复合物。BCKD 受 BCKD 激酶（BCKDK）调节，BCKDK 结合 BCKD 的 E2 亚基，磷酸化其 E1 亚基，并抑制酶活性。BCKD 复合物的抑制导致支链氨基酸和支链酮酸水平升高，这种堆积与心力衰竭、2 型糖尿病和非酒精性脂肪肝疾病有关。为了寻找 BCKDK 抑制剂用于这些疾病的潜在治疗，我们进行了 NMR 和虚拟片段筛选，并鉴定了在多个部位与 BCKDK 结合的含四唑片段。通过基于结构的虚拟筛选从这些片段扩展，发现血管紧张素受体阻滞剂类抗高血压药物和血管紧张素受体阻滞剂样化合物是有效的 BCKDK 抑制剂，这表明心力衰竭治疗结合 BCKDK 抑制和抗高血压的新途径。
