Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

Singh, Harbinder; Agrawal, Devendra K.

doi:10.1002/ddr.21971

Cited by 31 publications

(13 citation statements)

References 110 publications

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“…These receptors interact with Aβ and are known to involve in its transport and clearance. In vitro studies conceptualize the extracellular V domain of (RAGE) as a key domain for ligand binding (Singh and Agrawal 2022 ; Tolstova et al 2022 ; Yue et al 2022 ). Our results also confirm this prediction and as depicted in Fig.…”

Section: Discussionmentioning

confidence: 99%

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer’s Disease: Prospects for Designing New Therapeutics Compound

et al. 2023

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Memory impairment is a result of multiple factors including amyloid-beta (Aβ) accumulation. Several receptors are mediated for Aβ transport and signaling. Moreover, blood lipids are involved in Aβ signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aβ signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aβ. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer’s disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood–brain barrier (BBB).

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Section: Discussionmentioning

confidence: 99%

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer’s Disease: Prospects for Designing New Therapeutics Compound

et al. 2023

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“…The broad significance of RAGE–AGE interactions has only recently been receiving significant attention toward developing therapeutics for neurodegenerative diseases as well as other AGE-related diseases, including diabetes, atherosclerosis and cancers [ 18 , 71 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ]. RAGEs are involved in the onset of various pathological conditions, including cardiovascular diseases, diabetes, cancer and neurological disorders.…”

Section: Rage Antagonistsmentioning

confidence: 99%

“…The RAGE antagonists have received substantial interest in recent years toward developing therapeutic candidates. Recent reviews address the small molecule-based RAGE inhibitors, some of which, e.g., FPS-ZM1 (4-Chloro- N -cyclohexyl- N -(phenylmethyl)benzamide) and Azeliragon (3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H -imidazol-4-yl]phenoxy]- N , N -diethyl-1-propanamine), have gone onto clinical trials; although, currently none of the RAGE inhibitors/antagonists have been FDA-approved as therapeutics ( Figure 6 ) [ 18 , 50 , 71 ].…”

Section: Rage Antagonistsmentioning

confidence: 99%

“…The neuronal damage caused by AGE–RAGE interactions, followed by the activation of the inflammatory signaling cascade, is associated with the onset of various neurological disorders, including AD, TBI, ALS, and diabetic neuropathy and nephropathy. Furthermore, the AGE–RAGE interactions are also implicated in a variety of other inflammatory-associated diseases, including SARS-CoV-2 infections, diabetes, cancer, cardiovascular disease, inflammatory bowel disease, and bronchopulmonary dysplasia [ 1 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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RAGE Inhibitors in Neurodegenerative Diseases

2023

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Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer’s disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood–brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE–RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE–RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE–RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.

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“…The overall mechanisms of the HMGB1 ligand binding with RAGE to overexpress the inflammatory cytokines such as tumor necrosis factor (TNF-α) and interleukins (IL-6 and IL-1β) are depicted in Figure 2 . The detailed functional description of individual domains of RAGE was recently described in our publication [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Targeting the HMGB1/RAGE Axis in Inflammatory Diseases

Singh

Agrawal

2022

Molecules

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High mobility group box 1 (HMGB1) is a nuclear protein that can interact with a receptor for advanced glycation end-products (RAGE; a multi-ligand immunoglobulin receptor) and mediates the inflammatory pathways that lead to various pathological conditions, such as cancer, diabetes, neurodegenerative disorders, and cardiovascular diseases. Blocking the HMGB1/RAGE axis could be an effective therapeutic approach to treat these inflammatory conditions, which has been successfully employed by various research groups recently. In this article, we critically review the structural insights and functional mechanism of HMGB1 and RAGE to mediate inflammatory processes. More importantly, current perspectives of recent therapeutic approaches utilized to inhibit the communication between HMGB1 and RAGE using small molecules are also summarized along with their clinical progression to treat various inflammatory disorders. Encouraging results are reported by investigators focusing on HMGB1/RAGE signaling leading to the identification of compounds that could be useful in further clinical studies. We highlight the current gaps in our knowledge and future directions for the therapeutic potential of targeting key molecules in HMGB1/RAGE signaling in the pathophysiology of inflammatory diseases.

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Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

Cited by 31 publications

References 110 publications

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer’s Disease: Prospects for Designing New Therapeutics Compound

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer’s Disease: Prospects for Designing New Therapeutics Compound

RAGE Inhibitors in Neurodegenerative Diseases

Therapeutic Potential of Targeting the HMGB1/RAGE Axis in Inflammatory Diseases

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