Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification

Antwerpen, Pierre Van; Prévost, Martine; Zouaoui-Boudjeltia, Karim; Babar, Sajida; Legssyer, Ilham; Moreau, Patrick; Moguilevsky, Nicole; Vanhaeverbeek, Michel; Ducobu, Jean; Nève, Jean

doi:10.1016/j.bmc.2007.11.025

Cited by 24 publications

(48 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reliability of the docking procedure was previously assessed by comparing the docking of salicylhydroxamic acid with its position in the crystal structure of the MPO complex. 16 The best pose of 5-fluorotryptamine ( Figure 2A) featured stacking of the indole 6-membered ring onto the pyrrole ring D of the heme. Stacking was also observed in the crystal structure of the MPO structure in complex with salicylhydroxamic acid.…”

Section: Resultsmentioning

confidence: 99%

“…29 However, these results were only observed at high concentrations, rendering flufenamic acid unusable because of its toxic adverse effects at these doses. Analogous compounds were also investigated but none had better inhibitory activity, 16 likely because their negative charge dampened the interaction between MPO and anionic LDLs. 30 We, therefore, hypothesized that positively charged compounds could overcome this problem and in addition would allow more favorable interactions with anionic amino acid residues at the active site of MPO.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors

et al. 2010

Self Cite

View full text Add to dashboard Cite

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Then the absorbance of the solutions was measured at 412 nm with a microplate reader, and the curve of absorbance as a function of inhibitor concentration was plotted. IC 50 values were then determined by standard procedures, considering the absence of hydrogen peroxide as 100% inhibition and the absence of inhibitors as 0% inhibition [16,17].…”

Section: Determination Of Myeloperoxidase Activitymentioning

confidence: 99%

The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase

Franck

Aldib

Boudjeltia

et al. 2019

Chemico-Biological Interactions

Self Cite

View full text Add to dashboard Cite

A water-soluble curcumin lysinate incorporated into hydroxypropyl-β-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-β-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼10 7 M −1 s −1) but not for Compound II (∼10 3 M −1 s −1) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by πstacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-βcyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropylβ-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.

show abstract

“…radicals) apparently shift the enzyme out of the peroxidase cycle into the Compound III state. The latter can only be formed from ferric or ferrous MPO with activated oxygen (k6) or dioxygen (k7) respectively (Figure 1) [33]. Parameters such as charge and lipophilicity of compounds have already been evoked to explain similar results [17].…”

Section: Discussionmentioning

confidence: 86%

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

et al. 2017

Self Cite

View full text Add to dashboard Cite

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic inflammatory diseases. Because of the deleterious effects of circulating MPO released from phagocytosing neutrophils, there is a great interest in the development of new efficient and specific inhibitors. It has been demonstrated that the interaction between the inhibitor and the active site is not the only key factor playing a role in the inhibition. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening combined to drug-likeness filters. Starting from a set of 727,842 compounds, 30 molecules were selected by this virtual method and tested for inhibition of the chlorination activity of MPO. Twelve out of 30 compounds were found to have an IC50 less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (Zinc1) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (Zinc3) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that Zinc1 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration. Pharmacomodulation has been performed to optimize the activity of Zinc1.

show abstract

Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification

Cited by 24 publications

References 37 publications

Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors

Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors

The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

Contact Info

Product

Resources

About