Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus
Dzyurkevich M. S., Babkov D. A., Shtyrlin N. V., Mayka O. Y., Iksanova A. G., Vassiliev P. M., Balakin K. V., Spasov A. A., Tarasov V. V., Barreto G., Shtyrlin Y. G., Aliev G.
Scientific Reports
Vol.7, Issue1, Num.16072
Опубликовано: 2017
Тип ресурса: Статья
DOI:10.1038/s41598-017-16405-2
Аннотация:
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150[%] and 130[%]) were comparable to that of the reference agent PF-04937319 (~154[%]). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellit
Ключевые слова:
enzyme activator; glucokinase; pyridoxine; allosteric site; animal; chemistry; female; human; male; metabolism; molecular docking; non insulin dependent diabetes mellitus; rat; synthesis; toxicity testing; Allosteric Site; Animals; Diabetes Mellitus, Type 2; Enzyme Activators; Female; Glucokinase; Humans; Male; Molecular Docking Simulation; Pyridoxine; Rats; Toxicity Tests, Acute
Язык текста: Английский
ISSN: 2045-2322
Dzyurkevich M. S.
Babkov D. A.
Shtyrlin N. V.
Mayka O. Y.
Iksanova A. G.
Vassiliev P. M.
Balakin K. V. Konstantin Valeryevich 1970-
Spasov A. A.
Tarasov V. V. Vadim Vladimirovich 1987-
Barreto G.
Shtyrlin Y. G.
Aliev G. Gyumrakh 1958-
Дзюркевич М. С.
Бабков Д. А.
Штyрлин Н. В.
Майка О. Y.
Иксанова А. Г.
Вассилиев П. М.
Балакин К. В. Константин Валерьевич 1970-
Спасов А. А.
Тарасов В. В. Вадим Владимирович 1987-
Баррето Г.
Штyрлин Y. Г.
Алиев Г. Гюмрах 1958-
Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus
Текст визуальный непосредственный
Scientific Reports
Vol.7, Issue1 Num.16072
2017
Статья
enzyme activator glucokinase pyridoxine allosteric site animal chemistry female human male metabolism molecular docking non insulin dependent diabetes mellitus rat synthesis toxicity testing Allosteric Site Animals Diabetes Mellitus, Type 2 Enzyme Activators Female Glucokinase Humans Male Molecular Docking Simulation Pyridoxine Rats Toxicity Tests, Acute
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150[%] and 130[%]) were comparable to that of the reference agent PF-04937319 (~154[%]). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellit