Effects on Conformational States of the Rabbit Sodium/Glucose Cotransporter through Modulation of Polarity and Charge at Glutamine 457

Liu, Tiemin; Krofchick, Daniel; Silverman, Melvin

doi:10.1016/j.bpj.2008.09.045

Cited by 7 publications

(6 citation statements)

References 34 publications

(72 reference statements)

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“…Canagliflozin was found to interact with SGLT2 with 17 amino acid residues, namely, W289, Y290, V286, S460, L149, K154, T153, V157, D158, G79, F453, H80, N75, F98, E99, Q457and I456 ( Table 1 and Fig. Structure-function studies on hSGLT1 suggest that residue 457 i.e., Q457 interacts directly with sugar for its reabsorption [43][44][45]. In 2008, the crystal structure of Vibrio parahaemolyticus SGLT (vSGLT) clearly resolved the residues of the sugar binding site and it was found that one residue that directly interacts with the sugar is glutamine 428, which is equivalent to amino acid at position 457 in mammalian SGLT proteins [42].…”

Section: Resultsmentioning

confidence: 99%

Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated Neurological Disorders

Khan¹,

Ahmad²,

Tiwari³

et al. 2014

CNSNDDT

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The increasing worldwide prevalence of type 2 diabetes mellitus (T2DM) and associated neurological disorders (NDs), such as Alzheimer disease and Parkinson's disease, have raised concerns about increasing health care and financial burden. Due to the overwhelming growth rate of T2DM and its strong association with NDs, there is an ever-growing and an urgent need to improve the diagnosis and management of the disease. Major hurdles in the management of T2DM comprise of striving for glycemic targets, polypharmacy, patient adherence and clinical inertia. The challenges occurring in the treatment of T2DM are mainly attributed to the complex heterogeneous nature of the disease and its close association with a wide variety of neurological, metabolic and cardiovascular disorders. To overcome these challenges, authors propose to focus on the treatment strategies that employ shared pathogenesis and common molecular denominators involved in the aetiology of T2DM and associated NDs. Impaired insulin signalling (as a result of perturbed redox status), insulin resistance and mitochondrial dysfunction are key molecular events that may lead to the pathogenesis of T2DM and associated NDs. However, effective management of these therapeutic strategies requires holistic experimental evidence from animal as well as clinical human studies. Therefore, a shift in the treatment paradigm from single point glycemic control to shared pathogenesis control would be an ideal approach to combat the alarming progression of diabetes and associated NDs. Therapeutic interventions focused on shared molecular pathogenesis, along with effective glycemic control, may provide protection from associated NDs.

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Section: Resultsmentioning

confidence: 99%

Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated Neurological Disorders

Khan¹,

Ahmad²,

Tiwari³

et al. 2014

CNSNDDT

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“…The function of human SGLT1 protein is dramatically affected by amino acid at position 457. It has been shown that residue 457 (i.e., Q457) in human SGLT1 directly interacts with sugar for its reabsorption [ 39 , 40 ]. The amino acid sequences of SGLT1 and SGLT2 revealed that both of these proteins have glutamine at the residue 457 position, and glucose–galactose malabsorption occurs due to mutation in the glutamine residue (Q457) [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

et al. 2021

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The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium–glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (−)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH’s adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of −5.65 kcal/mol and 71.95 µM, −5.50 kcal/mol and 92.97 µM, and −5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.

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“…Interestingly, the amino acid at position 457 in human SGLT1 has been proven to cause a dramatic effect on the protein‐function. Briefly, Q457 is directly involved in proper reabsorption of the sugar in case of human SGLT1 [Liu et al, ]. Glutamine 457 mutations are well‐known to cause glucose‐galactose malabsorption.…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, Q457 is directly involved in proper reabsorption of the sugar in case of human SGLT1 [Liu et al, 2009]. Briefly, Q457 is directly involved in proper reabsorption of the sugar in case of human SGLT1 [Liu et al, 2009].…”

Section: Journal Of Cellular Biochemistrymentioning

confidence: 99%

Molecular Interaction of Anti‐Diabetic Drugs With Acetylcholinesterase and Sodium Glucose Co‐Transporter 2

Shakil

2017

J of Cellular Biochemistry

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Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) are the two disorders which are known to share pertinent pathological and therapeutic links. Sodium glucose co-transporter-2 (SGLT2) and Acetylcholinesterase (AChE) are established inhibition targets for T2DM and AD treatments, respectively. Reports suggest that anti-diabetic drugs could be used for AD treatment also. The present study used molecular docking by Autodock4.2 using our "Click-By-Click"-protocol, Ligplot1.4.3 and "change in accessible surface area (ΔASA)-calculations" to investigate the binding of two investigational anti-diabetic drugs, Ertugliflozin and Sotagliflozin to an established target (SGLT2) and a research target (human brain AChE). Sotagliflozin appeared more promising for SGLT2 as well as AChE-inhibition with reference to ΔG and Ki values in comparison to Ertugliflozin. The ΔG and Ki values for "Sotagliflozin:AChE-binding" were -7.16 kcal/mol and 5.6 μM, respectively while the same were found to be -8.47 kcal/mol and 0.62 μM, respectively for its interaction with SGLT2. Furthermore, "Sotagliflozin:SGLT2-interaction" was subjected to (un)binding simulation analyses by "Molecular-Motion-Algorithms." This information is significant as the exact binding mode, interacting amino acid residues and simulation results for the said interaction have not been described yet. Also no X-ray crystal is available for the same. Finally, the results described herein indicate that Sotagliflozin could have an edge over Ertugliflozin for treatment of Type 2 diabetes. Future design of drugs based on Sotagliflozin scaffolds for treatment of Type 2 and/or Type 3 diabetes are highly recommended. As these drugs are still in late phases of clinical trials, the results described herein appear timely. J. Cell. Biochem. 118: 3855-3865, 2017. © 2017 Wiley Periodicals, Inc.

show abstract

Effects on Conformational States of the Rabbit Sodium/Glucose Cotransporter through Modulation of Polarity and Charge at Glutamine 457

Cited by 7 publications

References 34 publications

Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated Neurological Disorders

Current Challenges to Overcome in the Management of Type 2 Diabetes Mellitus and Associated Neurological Disorders

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

Molecular Interaction of Anti‐Diabetic Drugs With Acetylcholinesterase and Sodium Glucose Co‐Transporter 2

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