Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111)

Zhang, Liping; Zhang, Hong; Zhao, Yiting; Li, Zhe; Chen, Shangke; Zhai, Jing; Chen, Yunyun; Xie, Wei; Wang, Zhong; Li, Qing; Zheng, Xuehua; Hu, Xiaopeng

doi:10.1016/j.febslet.2013.09.031

Cited by 76 publications

(59 citation statements)

References 31 publications

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“…The docking studies were carried out using GOLD v5.2.2 software (Genetic Optimization for Ligand Docking) [25,26] . The crystal structure of AKR1B10 (PDB code: 4I5X) [10] was downloaded from the protein data bank (www.rcsb.org). All water molecules were removed and hydrogen atoms were added to calculate the bond orders for the protein and ligand.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…All water molecules were removed and hydrogen atoms were added to calculate the bond orders for the protein and ligand. The orientations of all histidine tautomers were transformed into the ND1H protonation states, as in the crystal structure [10] . The binding site of the protein was defined for all the atoms within 10 Å of the co-crystallized ligand in the crystal structure.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Therefore, AKR1B10 plays a crucial role in carcinogenesis by promoting cell survival and metastasis, and its importance as a potential cancer drug target has been well documented. The crystal structure of AKR1B10 represents the typical (α/β) 8 barrel topology characteristic of the AKR superfamily proteins [1,10] . The active site is located at the C-terminal end of the barrel and a binding pocket is formed between external loops B and C. The NADP + is adjoined near the active site in a stretched conformation.…”

Section: Introductionmentioning

confidence: 99%

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Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

et al. 2015

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Aim: Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches. Methods: The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein-ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations. Results: The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10. Conclusion: Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.

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Section: Molecular Dockingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

et al. 2015

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“…This enzyme is involved in diabetic complications, and a variety of AKR1B1 inhibitors have been developed for the treatment of diabetic patients [21]. The clinical and preclinical data collected over decades by diabetologists would greatly assist the transition of these inhibitors to the clinic of ACC.…”

Section: Discussionmentioning

confidence: 99%

2D-DIGE proteomic analysis identifies new potential therapeutic targets for adrenocortical carcinoma

et al. 2015

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Adrenocortical carcinoma (ACC) is a rare aggressive tumor with poor prognosis when metastatic at diagnosis. The tumor biology is still mostly unclear, justifying the limited specificity and efficacy of the anti-cancer drugs currently available. This study reports the first proteomic analysis of ACC by using two-dimensional-differential-in-gel-electrophoresis (2D-DIGE) to evaluate a differential protein expression profile between adrenocortical carcinoma and normal adrenal. Mass spectrometry, associated with 2D-DIGE analysis of carcinomas and normal adrenals, identified 22 proteins in 27 differentially expressed 2D spots, mostly overexpressed in ACC. Gene ontology analysis revealed that most of the proteins concurs towards a metabolic shift, called the Warburg effect, in adrenocortical cancer. The differential expression was validated by Western blot for Aldehyde-dehydrogenase-6-A1,Transferrin, Fascin-1,Lamin A/C,Adenylate-cyclase-associated-protein-1 and Ferredoxin-reductase. Moreover, immunohistochemistry performed on paraffin-embedded ACC and normal adrenal specimens confirmed marked positive staining for all 6 proteins diffusely expressed by neoplastic cells, compared with normal adrenal cortex.In conclusion, our preliminary findings reveal a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes, thus suggesting the Warburg effect also occurs in ACC. These proteins may represent promising novel ACC biomarkers and potential therapeutic targets if validated in larger cohorts of patients.

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“…Moreover, novel cocrystal preparations of epalrestat were also reported, including choline hydrogen diepalrestat, betaine hydrogen diepalrestat and choline hydrogen diacid cocrystal of epalrestat (WO2010028132, WO2010011926, US2015057319) [92][93][94]. Nevertheless, epalrestat was also reported to inhibit AKR1B10 [73]. Except for epalrestat, the ARI fidarestat(6) could also be used as a therapeutic drug for its low in vivo side effects [95].…”

Section: Aldose Reductase Inhibitors (Aris)mentioning

confidence: 99%

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Li¹,

He²,

Luo³

et al. 2016

PRA

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Cytosolic NADPH-dependent reductase AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily. This enzyme is normally expressed in the gastrointestinal tract. However, it is overexpressed in many solid tumors, such as hepatocarcinoma, lung cancer and breast cancer. AKR1B10 may play a role in the formation and development of carcinomas through multiple mechanisms including detoxification of cytotoxic carbonyls, modulation of retinoic acid level, and regulation of cellular fatty acid synthesis and lipid metabolism. Studies have suggested that AKR1B10 may be a useful biomarker for cancer diagnosis and a potential target for cancer treatment. Over the last decade, a number of AKR1B10 inhibitors including aldose reductase inhibitors (ARIs), endogenous substances, natural-based derivatives and synthetic compounds have been developed, which could be novel anticancer drugs. This review provides an overview on related articles and patents about AKR1B10 inhibitors, with a focus on their inhibition selectivity and mechanism of function.

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Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111)

Cited by 76 publications

References 31 publications

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

2D-DIGE proteomic analysis identifies new potential therapeutic targets for adrenocortical carcinoma

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

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