Molecular Dynamics Simulations of Trichomonas vaginalis Ferredoxin Show a Loop-Cap Transition

Weksberg, Tiffany E.; Lynch, Gillian C.; Krause, Kurt L.; Pettitt, B. Montgomery

doi:10.1529/biophysj.106.088096

Cited by 5 publications

(4 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In T. vaginalis, TvFd (Trichomonas vaginalis ferredoxin) is a hydrogenosomal protein involved in the bioreduction of metronidazole. TvFd is a 9.8 kD protein constituted by 93 residues containing a [2Fe-2S] cluster responsible for electron transfer reactions [31,32].…”

Section: Molecular Dockingmentioning

confidence: 99%

Synthesis, in vitro Antitrichomonal Activity, and Docking Study of N-[(4-substituted phenyl)-1,3-thiazol-2-yl]-4-substituted Benzenesulfonamides

M. Carballo,

Peniche-Pavía,

Quijano-Quiñones

et al. 2024

J. Mex. Chem. Soc.

View full text Add to dashboard Cite

Infection by Trichomonas vaginalis has a high incidence/prevalence worldwide. It has been associated with a predisposition to cervical neoplasia or prostate cancer and an increased risk of acquisition of human papillomavirus (HPV) and human immunodeficiency virus (HIV). Besides, resistance to the drugs used for trichomoniasis treatment has increased in the last 30 years. Herein, thirteen phenylthiazolylbenzene sulfonamides were synthesized and evaluated for their in vitro activity against Trichomonas vaginalis. Among them, four derivatives showed higher anti-trichomonal activity than metronidazole (IC50 = 0.93 µM), while their cytotoxicity levels were not significant. These compounds were subject to molecular docking studies using Trichomonas vaginalis ferredoxin as target. The results revealed that the orientation of the nitro group of the active derivatives is toward [2Fe-2S], the cluster responsible for high reactive oxygen species generation. Finally, it was evident that the presence of a nitro group in the structure of the synthesized phenylthiazolylbenzene sulfonamides is essential for their trichomonicidal activity. Resumen. A nivel mundial la infección por Trichomonas vaginalis tiene una alta incidencia/prevalencia y se ha asociado con una predisposición a padecer neoplasia cervical o cáncer de próstata, así como a generar un mayor riesgo de adquirir el virus del papiloma humano (VPH) y el virus de la inmunodeficiencia humana (VIH). Además, en los últimos 30 años, la resistencia a los fármacos utilizados para el tratamiento de la tricomoniasis ha aumentado. En el presente trabajo, trece sulfonamidas de feniltiazolilbenceno fueron sintetizadas y evaluadas in vitro contra Trichomonas vaginalis. Cuatro de ellas exhibieron una actividad anti-tricomonas mayor que el metronidazol (CI50 = 0.93 µM), a la vez que citotoxicidad no significativa. Por tal motivo, estos compuestos fueron sometidos a estudios de acoplamiento molecular utilizando como diana a la ferredoxina de T. vaginalis. Los resultados revelaron que la orientación del grupo nitro de los derivados activos está dirigida hacia el grupo [2Fe-2S], responsable de la generación de especies de oxígeno altamente reactivas. Finalmente, se evidenció que la presencia de al menos un grupo nitro en la estructura de las sulfonamidas de feniltiazolilbenceno sintetizadas es esencial para su actividad tricomonicida.

show abstract

Section: Molecular Dockingmentioning

confidence: 99%

Synthesis, in vitro Antitrichomonal Activity, and Docking Study of N-[(4-substituted phenyl)-1,3-thiazol-2-yl]-4-substituted Benzenesulfonamides

M. Carballo,

Peniche-Pavía,

Quijano-Quiñones

et al. 2024

J. Mex. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…Compound 1 showed a polar contact with Ser-238 (Figure 2), which may be due to the higher flexibility of the cyclohexane, facilitating a better fit in the binding cavity for the imidazole ring. For PFOR, we studied the previously proposed site for metronidazole [14], around Thr-37, close to the catalytic site. Docking simulations showed that metronidazole and the newly designed compounds have a suitable orientation for the binding site, this is, with the nitro group pointing toward the [2Fe-2S] core.…”

Section: Dockingmentioning

confidence: 99%

“…Docking poses provide a plausible explanation for the lower activity against T. vaginalis of bulky-substituted compounds on the R-position, as the size of the site could prevent the proper orientation of the 5-nitroimidazole scaffold. For PFOR, we studied the previously proposed site for metronidazole [14], around Thr-37, close to the catalytic site. Docking simulations showed that metronidazole and the newly designed compounds have a suitable orientation for the binding site, this is, with the nitro group pointing toward the [2Fe-2S] core.…”

Section: Dockingmentioning

confidence: 99%

Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies

et al. 2020

View full text Add to dashboard Cite

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1–5) and secnidazole (6–10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1–10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1–10, secnidazole, and metronidazole onto the ligand binding site of pyruvate–ferredoxin oxidoreductase of T. vaginalis and the modeled β-tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.

show abstract

“…In this work, molecular dynamics simulation, which has been proved to be a useful method of discovering flexibility and tracing conformational changes at an atomic level [35][36][37], is used to reproduce the systems containing both Na + and K + ions and the simulation can show some interesting subtle results that cannot be proved by experiments [38]. The averaged peptide structures induced by mixed inorganic salts are compared and the competition between the two cations is investigated as the concentration ratio changes.…”

Section: Introductionmentioning

confidence: 99%

Mixed-salt effects on the conformation of a short salt-bridge-formingαhelix: A simulation study

2014

View full text Add to dashboard Cite

The structure of a single alanine-based ACE-AEAAAKEAAAKA-NH2 peptide in explicit aqueous solutions with mixed inorganic salts (NaCl and KCl) is investigated by using molecular simulations. The concentration of Na(+), c(Na(+)), varies from 0.0M to 1.0M, whereas the concentration of K(+) is 1-c(Na(+)). The simulated peptide is very sensitive to the change of concentration ratio between Na(+) and K(+). When the concentration ratio between Na^{+} and K^{+} is changed from 0.5/0.5, the structure of the peptide becomes loose or disordered. This specific phenomenon is confirmed via checking the changes of helix parameters and mapping the free energy along different coordinates. The higher normalized probability of forming direct and indirect salt bridges between residues Glu7(+) and Lys11(+) and the smallest probability of forming ringlike structures should be responsible for the stabilized helix structure in the 0.5 Na(+)/0.5 K(+) solution. Furthermore, a noticeable conformational transition from an extended helix to an α helix is found in the 0.5 Na(+)/0.5 K(+) solution, where a local ion cloud shows that some Na(+) ions in the inner shells are still directly binding with the peptide, while K(+) in the outer shells are moving into the inner shells, keeping the peptide in the collapsed state.

show abstract

Molecular Dynamics Simulations of Trichomonas vaginalis Ferredoxin Show a Loop-Cap Transition

Cited by 5 publications

References 47 publications

Synthesis, in vitro Antitrichomonal Activity, and Docking Study of N-[(4-substituted phenyl)-1,3-thiazol-2-yl]-4-substituted Benzenesulfonamides

Synthesis, in vitro Antitrichomonal Activity, and Docking Study of N-[(4-substituted phenyl)-1,3-thiazol-2-yl]-4-substituted Benzenesulfonamides

Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies

Mixed-salt effects on the conformation of a short salt-bridge-formingαhelix: A simulation study

Contact Info

Product

Resources

About