Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

Miyamoto, Shuichi

doi:10.1273/cbij.2.74

Cited by 50 publications

(25 citation statements)

References 54 publications

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“…Inhibiting AR and thus preventing the entry of glucose into the sorbitol pathway can reduce the damaging effects of late-onset diabetic disorders [4]. Considerable effort has been spent in the discovery and optimization of potent AR inhibitors (ARIs), resulting in a large variety of inhibitor-compound classes [5]. However, so far only a very small number of compounds has met the criteria of sufficient potency, oral activity and an acceptable side-effect profile.…”

Section: Introductionmentioning

confidence: 99%

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Klebe

Krämer

Sotriffer

2004

Cellular and Molecular Life Sciences (CMLS)

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Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.

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Section: Introductionmentioning

confidence: 99%

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Klebe

Krämer

Sotriffer

2004

Cellular and Molecular Life Sciences (CMLS)

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“…The hydrophobic region of the inhibitor binds in a ''specificity'' hydrophobic pocket in the active site, which is accessible after a conformational change of the enzyme. 47 The important structural features of aldose reductase inhibitors include the presence of polar and nonpolar hydrophobic system, with polar groups attached to the hydrophobic ring system. The polar moiety of a inhibitor binds in a conserved active anion-binding site (catalytic site) and also interacts with NADP + (nicotinamide ring) of the coenzyme by forming hydrogen bonds with Tyr48, His110, and Trp111 residues of the coenzyme (present within the active binding site) to hold the polar moiety firmly in the catalytic site.…”

Section: Berberine Versus Palmatinementioning

confidence: 99%

“…54 6. Alkaloids such as discretine (45), desmorostratine (46), discretine N-oxide (47), dehydrodiscretine (48), pseudocolumbamine (49), and predicentrin (50) (Fig. 10) present in the methanolic extract of stem bark of Desmos rostrata.…”

Section: Future Directionsmentioning

confidence: 99%

Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine

Gupta

Singh

Jaggi

2014

The Journal of Alternative and Complementary Medicine

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Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phyto-constituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.

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“…It is known, that the thioxo group in the rhodanine motif is a carboxylic acid bioisoster by size with low electronegativity and possesses the ability to build hydrogen bonds [13,14]. So far, rhodanine-containing compounds have been developed as promising antitumor, antimicrobial, anti-inflammatory, antidiabetic agents, etc.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of Novel Rhodanine‐containing Sorafenib Analogs as Potential Antitumor Agents

Zhai

Zhong

et al. 2011

Archiv der Pharmazie

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A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity superior to the reference drug sorafenib, especially the most promising compound 7r (with the IC(50) value of 0.8, 1.3 and 2.8 µM against A549, H460 and HT29 cell lines, respectively). The activity was found to strongly depend on the substitution pattern of the rhodanine motif at C-5″ position. Results suggested that this series of compounds could serve as the bases for the development of novel antitumor agents.

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Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

Cited by 50 publications

References 54 publications

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine

Design, Synthesis and Evaluation of Novel Rhodanine‐containing Sorafenib Analogs as Potential Antitumor Agents

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