Structural characterization of the aquaporin inhibitor 2-nicotinamido-1,3,4-thiadiazole

Burnett, Marianne E.; Johnston, Hannah M.; Green, Kayla N.

doi:10.1107/s2053229615021130

Cited by 7 publications

(12 citation statements)

References 18 publications

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“…The most stable structure of TGN-020 in our unbiased approach represents a novel tautomer of the compound ( Fig.1Biii ). This one differs from the described X-ray, IR, and NMR structure ( 20 ), where TGN-020 makes strong interactions with itself (X-ray and IR), and in the aprotic solvent DMSO (NMR). Notably, the carbonyl group of the amide points to the sulfur side of the thiadiazole in this compound, in agreement with our predictions for TGN-020.…”

Section: Resultscontrasting

confidence: 56%

“…1Biii). This one differs from the described X-ray, IR, and NMR structure (20), where TGN-020 makes strong interactions with itself (X-ray and IR), and in the aprotic solvent DMSO (NMR).…”

Section: Identification Of An Electronic Homologue Of Tgn-020contrasting

confidence: 56%

“…Notably, the carbonyl group of the amide points to the sulfur side of the thiadiazole in this compound, in agreement with our predictions for TGN-020. Compared to the X-ray structure of TGN-020 ( 20 ), the hydrogen bonding pattern in the new tautomer is different in the amide and thiadiazole parts ( Fig.1C-D ). The new pattern was used as a template to screen for electronic bioisosteres, i.e., molecules with similar sterics and electron distribution by using COSMOsim-3D, which is able to identify such bioisosteres with high confidence ( 15, 16 ) by aligning and comparing their COSMO-RS σ-surfaces.…”

Section: Resultsmentioning

confidence: 89%

“…From these contrasting findings, the search continues for a specific and potentially clinically relevant inhibitor of AQP4 with the same inhibitory effect no matter the test system. We reanalysed the structure of TGN-020 ( 20 ) and identified a novel tautomer. As evident from the COSMO-RS sigma-surface, the ORI-TRN-002 compound provides the new hydrogen bonding pattern and supports the novel tautomer as the viable target structure for AQP4.…”

Section: Discussionmentioning

confidence: 99%

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Towards new AQP4 inhibitors: ORI-TRN-002

Thormann,

Traube,

Yehia

et al. 2023

Preprint

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Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated elevated intracranial pressure, yet they primarily alleviate pressure rather than preventing edema formation. Prophylactic anti-edema therapy necessitates novel drugs targeting edema formation. Aquaporin 4 (AQP4), an abundantly expressed water pore in mammalian glia and ependymal cells, has been proposed to be involved in cerebral edema formation. A series of novel compounds have been tested for their potential inhibitory effects on AQP4. However, selectivity, toxicity, functional inhibition, sustained therapeutic concentration, and delivery into the central nervous system are major challenges. Employing extensive DFT calculations, we identified a previously unreported thermodynamically stable tautomer of the recently identified AQP4-specific inhibitor TGN-020. This novel form, featuring a distinct hydrogen bonding pattern, served as a template for a COSMOsim-3D based virtual screen of proprietary compounds from Origenis™. The screening identified ORI-TRN-002, an electronic homologue of TGN-020, demonstrating high solubility and low protein binding. Evaluating ORI-TRN-002 on AQP4-expressingXenopus laevisoocytes using a high-resolution volume recording system revealed an IC50of 2.9 ± 0.6 μM, establishing it as a novel AQP4 inhibitor. ORI-TRN-002 exhibits superior solubility and free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising antiedema therapy for treating cerebral edema in the future.

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Section: Resultscontrasting

confidence: 56%

“…1Biii). This one differs from the described X-ray, IR, and NMR structure (20), where TGN-020 makes strong interactions with itself (X-ray and IR), and in the aprotic solvent DMSO (NMR).…”

Section: Identification Of An Electronic Homologue Of Tgn-020contrasting

confidence: 56%

Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Towards new AQP4 inhibitors: ORI-TRN-002

Thormann,

Traube,

Yehia

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The most stable structure of TGN-020 in our unbiased approach represents a novel tautomer of the compound (Figure 1B(iii)). This one differs from the described X-ray, IR, and NMR structure [20], where TGN-020 makes strong interactions with itself (X-ray and IR) in the aprotic solvent DMSO (NMR). Notably, the carbonyl group of the amide points to the sulfur side of the thiadiazole in this compound, which is in agreement with our predictions for TGN-020.…”

Section: Identification Of An Electronic Homologue Of Tgn-020contrasting

confidence: 57%

Toward New AQP4 Inhibitors: ORI-TRN-002

Thormann,

Traube,

Yehia

et al. 2024

IJMS

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Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated elevated intracranial pressure, yet they primarily alleviate pressure rather than prevent edema formation. Prophylactic anti-edema therapy necessitates novel drugs targeting edema formation. Aquaporin 4 (AQP4), an abundantly expressed water pore in mammalian glia and ependymal cells, has been proposed to be involved in cerebral edema formation. A series of novel compounds have been tested for their potential inhibitory effects on AQP4. However, selectivity, toxicity, functional inhibition, sustained therapeutic concentration, and delivery into the central nervous system are major challenges. Employing extensive density-functional theory (DFT) calculations, we identified a previously unreported thermodynamically stable tautomer of the recently identified AQP4-specific inhibitor TGN-020 (2-(nicotinamide)-1,3,4-thiadiazol). This novel form, featuring a distinct hydrogen-bonding pattern, served as a template for a COSMOsim-3D-based virtual screen of proprietary compounds from Origenis™. The screening identified ORI-TRN-002, an electronic homologue of TGN-020, demonstrating high solubility and low protein binding. Evaluating ORI-TRN-002 on AQP4-expressing Xenopus laevis oocytes using a high-resolution volume recording system revealed an IC50 of 2.9 ± 0.6 µM, establishing it as a novel AQP4 inhibitor. ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema in the future.

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