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(-)-Kusunokinin as a Potential Aldose Reductase Inhibitor: Equivalency Observed via AKR1B1 Dynamics Simulation.

ABSTRACT: (-)-Kusunokinin performed its anticancer potency through CFS1R and AKT pathways. Its ambiguous binding target has, however, hindered the next development phase. Our study thus applied molecular docking and molecular dynamics simulation to predict the protein target from the pathways. Among various candidates, aldo-keto reductase family 1 member B1 (AKR1B1) was finally identified as a (-)-kusunokinin receptor. The predicted binding affinity of (-)-kusunokinin was better than the selected aldose reductase inhibitors (ARIs) and substrates. The compound also had no significant effect on AKR1B1 conformation. An intriguing AKR1B1 efficacy, with respect to the known inhibitors (epalrestat, zenarestat, and minalrestat) and substrates (UVI2008 and prostaglandin H₂), as well as a similar interactive insight of the enzyme pocket, pinpointed an ARI equivalence of (-)-kusunokinin. An aromatic ring and a ?-butyrolactone ring shared a role with structural counterparts in known inhibitors. The modeling explained that the aromatic constituent contributed to ?-? attraction with Trp111. In addition, the ?-butyrolactone ring bound the catalytic His110 using hydrogen bonds, which could lead to enzymatic inhibition as a consequence of substrate competitiveness. Our computer-based findings suggested that the potential of (-)-kusunokinin could be furthered by in vitro and/or in vivo experiments to consolidate (-)-kusunokinin as a new AKR1B1 antagonist in the future.

SUBMITTER: Tanawattanasuntorn T

PROVIDER: S-EPMC7807751 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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(-)-Kusunokinin as a Potential Aldose Reductase Inhibitor: Equivalency Observed via AKR1B1 Dynamics Simulation.

Tanawattanasuntorn Tanotnon T Thongpanchang Tienthong T Rungrotmongkol Thanyada T Hanpaibool Chonnikan C Graidist Potchanapond P Tipmanee Varomyalin V

ACS omega 20201221 1

(-)-Kusunokinin performed its anticancer potency through CFS1R and AKT pathways. Its ambiguous binding target has, however, hindered the next development phase. Our study thus applied molecular docking and molecular dynamics simulation to predict the protein target from the pathways. Among various candidates, aldo-keto reductase family 1 member B1 (AKR1B1) was finally identified as a (-)-kusunokinin receptor. The predicted binding affinity of (-)-kusunokinin was better than the selected aldose r ...[more]

PMID: 33458512

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Project description:IntroductionPGF2α may be involved in the regulation of adipose tissue function.Objectives1) To examine PGF2α release by primary preadipocytes, mature adipocytes and whole tissue explants from the subcutaneous and omental fat compartments; 2) To assess which PGF synthase is the most relevant in human adipose tissue.MethodsFat samples were obtained by surgery in women. PGF2α release by preadipocytes, adipocytes and explants under stimulation by TNF-α, IL-1β or both was measured. Messenger RNA expression levels of AKR1B1 and AKR1C3 were measured by RT-PCR in whole adipose tissue and cytokine-treated preadipocytes. The effect of AKR1B1 inhibitor ponalrestat on PGF2α synthesis was investigated.ResultsPGF2α release was significantly induced in response to cytokines compared to control in omental (p = 0.01) and to a lesser extent in subcutaneous preadipocytes (p = 0.02). Messenger RNA of COX-2 was significantly higher in omental compared to subcutaneous preadipocytes in response to combined TNF-α and IL-1β (p = 0.01). Inflammatory cytokines increased AKR1B1 mRNA expression and protein levels (p≤0.05), but failed to increase expression levels of AKR1C3 in cultured preadipocytes. Accordingly, ponalrestat blunted PGF2α synthesis by preadipocytes in basal and stimulated conditions (p≤0.05). Women with the highest PGF2α release by omental adipocytes had a higher BMI (p = 0.05), waist circumference (p≤0.05) and HOMAir index (p≤0.005) as well as higher mRNA expression of AKR1B1 in omental (p<0.10) and subcutaneous (p≤0.05) adipose tissue compared to women with low omental adipocytes PGF2α release. Positive correlations were observed between mRNA expression of AKR1B1 in both compartments and BMI, waist circumference as well as HOMAir index (p≤0.05 for all).ConclusionPGF2α release by omental mature adipocytes is increased in abdominally obese women. Moreover, COX-2 expression and PGF2α release is particularly responsive to inflammatory stimulation in omental preadipocytes. Yet, blockade of PGF synthase AKR1B1 inhibits most of the PGF2α release.

Dataset Information

(-)-Kusunokinin as a Potential Aldose Reductase Inhibitor: Equivalency Observed via AKR1B1 Dynamics Simulation.

Publications

(-)-Kusunokinin as a Potential Aldose Reductase Inhibitor: Equivalency Observed via AKR1B1 Dynamics Simulation.

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