AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone DOI Open Access
Assmaa ElSheikh, Camden Driggers, Ha H. Truong

и другие.

Опубликована: Дек. 11, 2024

Pancreatic K ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility impaired CHI is hindered by high-affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet® followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC 50 ) ~ 9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared high affinity inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone DOI Open Access
Assmaa ElSheikh, Camden Driggers, Ha H. Truong

и другие.

Опубликована: Март 11, 2025

Pancreatic K ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility impaired CHI is hindered by high-affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet® followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC 50 ) ∼ 9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared high affinity inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

Процитировано

0
AI-based discovery and cryoEM structural elucidation of a KATP channel pharmacochaperone DOI Creative Commons
Assmaa ElSheikh, Camden Driggers, Ha H. Truong

и другие.

eLife, Год журнала: 2025, Номер 13

Опубликована: Март 26, 2025

Pancreatic K ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC 50 ) ~9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

Процитировано

0
AI-Based Discovery and CryoEM Structural Elucidation of a KATPChannel Pharmacochaperone DOI Creative Commons
Assmaa ElSheikh, Camden Driggers,

Ha H. Truong

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 5, 2024

Pancreatic KATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility impaired CHI is hindered by high-affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet® followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC50) ~ 9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared high affinity inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

Процитировано

0
AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone DOI Open Access
Assmaa ElSheikh, Camden Driggers, Ha H. Truong

и другие.

Опубликована: Дек. 11, 2024

Pancreatic KATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC50) ~9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

Процитировано

0
AI-Based Discovery and CryoEM Structural Elucidation of a KATP Channel Pharmacochaperone DOI Open Access
Assmaa ElSheikh, Camden Driggers, Ha H. Truong

и другие.

Опубликована: Дек. 11, 2024

Pancreatic K ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the opener diazoxide, mainstay medical therapy for CHI. Current clinically used inhibitors have been shown act as pharmacochaperones and restore surface expression of mutants; however, their therapeutic utility impaired CHI is hindered by high-affinity binding, which limits functional recovery rescued channels. Recent structural studies channels employing cryo-electron microscopy (cryoEM) revealed a promiscuous pocket where several known bind. The knowledge provides framework discovering with desired reversible inhibitory effects permit Using an AI-based virtual screening technology AtomNet® followed validation, we identified novel compound, termed Aekatperone, exhibits chaperoning on mutations. Aekatperone reversibly inhibits activity half-maximal concentration (IC 50 ) ~ 9 μM. Mutant cell showed upon washout compound. CryoEM structure bound distinct binding features compared high affinity inhibitor pharmacochaperones. Our findings unveil pharmacochaperone enabling promising caused defects.

Язык: Английский

Процитировано

0