A Series of Natural Flavonoids as Thrombin Inhibitors: Structure-activity relationships

Liu, Li; Ma, Hongyue; Yang, Nian‐Yun; Tang, Yuping; Guo, Jianming; Tao, Weiwei; Duan, Jin‐Ao

doi:10.1016/j.thromres.2010.08.006

Cited by 91 publications

(71 citation statements)

References 26 publications

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“…However, they may also cause serious side effects like hemorrhage [7]. For this reason, searching new thrombin inhibitors from natural sources has been recognized as a viable and effective alternative strategy for the therapy of thromboembolic diseases [8].…”

Section: Introductionmentioning

confidence: 99%

Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach

Song

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Section: Introductionmentioning

confidence: 99%

Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach

Song

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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“…Consistently, baicalein (a flavone) has been found to have a high TraR (a LuxR homologue of A. tumefaciens) docking score and to affect TraR stability, while baicalin (the 7-glucuronide of baicalein) has been found to have a low docking score and no effect on the stability of the TraR protein (Zeng et al, 2008), suggesting that the steric hindrance of glycosylated flavonoid moieties might indeed affect their capacity to interact with their targets. Modifying the hydroxylation, methoxylation and glycosylation status of flavonoids is well known to affect many of their biological activities, underlining the importance of the relationship between their precise structure and their biological properties (Halbwirth, 2010;Jiang et al, 2010;Liu et al, 2010;Pourcel et al, 2007;Shimada et al, 2010).Finally, a more detailed investigation of the importance of the various radicals and rings required for the anti-QS activity of flavanones via quantitative structure-activity relationship (QSAR) analysis might shed light on the chemical positions that can be modified in flavonoids that have anti-QS activities at high concentrations only, to confer anti-QS activity upon antimicrobial flavonoids or to modify promising QS inhibitors to obtain more potent compounds. This QSAR analysis could also serve for the rational design of anti-QS compounds through combinatorial chemistry.…”

mentioning

confidence: 99%

The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1

et al. 2011

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Preliminary screening of the Malagasy plant Combretum albiflorum for compounds attenuating the production of quorum sensing (QS)-controlled virulence factors in bacteria led to the identification of active fractions containing flavonoids. In the present study, several flavonoids belonging to the flavone, flavanone, flavonol and chalcone structural groups were screened for their capacity to reduce the production of QS-controlled factors in the opportunistic pathogen Pseudomonas aeruginosa (strain PAO1). Flavanones (i.e. naringenin, eriodictyol and taxifolin) significantly reduced the production of pyocyanin and elastase in P. aeruginosa without affecting bacterial growth. Consistently, naringenin and taxifolin reduced the expression of several QS-controlled genes (i.e. lasI, lasR, rhlI, rhlR, lasA, lasB, phzA1 and rhlA) in P. aeruginosa PAO1. Naringenin also dramatically reduced the production of the acylhomoserine lactones N-(3-oxododecanoyl)-Lhomoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), which is driven by the lasI and rhlI gene products, respectively. In addition, using mutant strains deficient for autoinduction (DlasI and DrhlI) and LasR-and RhlR-based biosensors, it was shown that QS inhibition by naringenin not only is the consequence of a reduced production of autoinduction compounds but also results from a defect in the proper functioning of the RlhR-C4-HSL complex. Widely distributed in the plant kingdom, flavonoids are known for their numerous and determinant roles in plant physiology, plant development and in the success of plant-rhizobia interactions, but, as shown here, some of them also have a role as inhibitors of the virulence of pathogenic bacteria by interfering with QS mechanisms. INTRODUCTIONIn many pathogenic bacteria the production of virulence factors is triggered in a population density-dependent manner through quorum sensing (QS), a cell-to-cell communication mechanism that enables bacteria to coordinate virulence factor production by means of the synthesis, release and perception of small diffusible molecules called autoinducers (Antunes et al., 2010;Bjarnsholt et al., 2010;Case et al., 2008;Ng & Bassler, 2009). For instance, in the plant and mammal opportunistic pathogen Pseudomonas aeruginosa, two main QS systems (lasI/R and rhlI/R), responsible for the synthesis and perception of the acylhomoserine lactones (AHLs) N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), respectively , control the expression Abbreviations: AHL, acylhomoserine lactone; C4-HSL, N-butanoyl-Lhomoserine lactone; ESI-MS, electrospray ionization-MS; HHL, Nhexanoyl-L-homoserine lactone; 3-oxo-C12-HSL, N-(3-oxododecanoyl)-L-homoserine lactone; PI, propidium iodide; QS, quorum sensing.3These authors contributed equally to this work. of an arsenal of virulence factors. The transcription factors LasR and RhlR interact with and are activated by 3-oxo-C12-HSL and C4-HSL, respectively, triggering the production of biofilms, LasB elastase...

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“…According to the literature, some of these flavonoids present a significant inhibitory profile against thrombin due to the presence of hydroxyl groups that mediate binding to thrombin aminoacid residues. Moreover, thrombin inhibition has also been shown to be positively correlated to the number of hydroxyl groups present in the flavonoid moiety [38]. This particular feature has been correlated with the inhibition of multi-subunit proteases complex such as the proteasome [36] and smaller serine proteases such as thrombin and Dengue virus NS2B-S3 [28,39].…”

Section: Resultsmentioning

confidence: 99%

Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic

et al. 2017

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Thrombosis related diseases are among the main causes of death and incapacity in the world. Despite the existence of antithrombotic agents available for therapy, they still present adverse effects like hemorrhagic risks which justify the search for new options. Recently, pachydictyol A, isopachydictyol A, and dichotomanol, three diterpenes isolated from Brazilian marine brown alga Dictyota menstrualis were identified as potent antithrombotic molecules through inhibition of thrombin, a key enzyme of coagulation cascade and a platelet agonist. Due to the biotechnological potential of these marine metabolites, in this work we evaluated their binding mode to thrombin in silico and identified structural features related to the activity in order to characterize their molecular mechanism. According to our theoretical studies including structure-activity relationship and molecular docking analysis, the highest dipole moment, polar surface area, and lowest electronic density of dichotomanol are probably involved in its higher inhibition percentage towards thrombin catalytic activity compared to pachydictyol A and isopachydictyol A. Interestingly, the molecular docking studies also revealed a good shape complementarity of pachydictyol A and isopachydictyol A and interactions with important residues and regions (e.g., H57, S195, W215, G216, and loop-60), which probably justify their thrombin inhibitor effects demonstrated in vitro. Finally, this study explored the structural features and binding mode of these three diterpenes in thrombin which reinforced their potential to be further explored and may help in the design of new antithrombotic agents.

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A Series of Natural Flavonoids as Thrombin Inhibitors: Structure-activity relationships

Cited by 91 publications

References 26 publications

Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach

Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach

The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1

Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic

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