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Volume 21, Issue 18
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Objective

Phosphodiesterase-5 (PDE5) is an enzyme that promotes the degradation of cGMP in the blood, leading to a restriction in regulating blood flow in the penis, thereby reducing cGMP causing difficulties for men in achieving hardness (erectile dysfunction). Natural products with fewer side effects are being developed in many different treatment strategies and are necessary today. The current study aims to evaluate this enzyme's inhibitory potential and marine xanthones through computational models.

Methods

The database of marine xanthones was collected from previously published literature. Protein structures were downloaded from the RCSB protein data bank (PDB ID: 1UDT). Molecular docking studies were performed using the AutoDock Vina v1.2.3 program to conduct screening. Molecular dynamics simulations were carried out with the GROMACS program to assess structural stability, and gmx_MMPBSA was used to make free-binding energy calculations for each PDE5 protein complex with potential compounds. Furthermore, Density Functional Theory (DFT) was applied in this study to calculate the atomic properties of the molecules based on quantum mechanics using the Gaussian 09 program.

Results

Molecular docking revealed that 21 compounds (staprexanthone A (69), emerixanthone E (89), emerixanthone A (90), emerixanthone C (91), varixanthone (92), aspergixanthone H (95), austocystin L (98), austocystin M (99), emerixanthone D (109), 15-acetyl tajixanthone hydrate (117), tajixanthone hydrate (118), 16-chlorotajixanthone (119), citreamicin ε A (131), citreamicin ε B (132), engyodontochone A (146), citreamicin θ B (151), citreaglycon A (152), dehydrocitreaglycon A (153), neocitreamicin I (159), citreamicin α (161), ukixanthomycin A (165) had superior binding affinities (ΔG < -11 kcal/mol) compared to the control inhibitor. Molecular dynamics confirmed the stability of the protein-ligand complexes. MM/GBSA analysis showed nine compounds (91, 98, 109, 118, 119, 151, 159, 161, 131) had binding energies comparable to or better than sildenafil. Quantum mechanical estimates indicated their potential as electron donors and acceptors, highlighting their antagonistic potential.

Conclusion

These promising marine xanthones warrant further research to assess their PDE5 inhibitory activity and . This could provide valuable insights for developing new natural resource-based drugs to prevent or treat erectile dysfunction.

© 2024 Bentham Science Publishers
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2025-01-02
2025-06-20

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Marine Xanthones as Promising Phosphodiesterase-5 Inhibitors in the Management of Erectile Dysfunction: An In silico Approach
Letters in Drug Design & Discovery 21, 4544 (2024); https://doi.org/10.2174/0115701808356442241221183358
/content/journals/lddd/10.2174/0115701808356442241221183358
/content/journals/lddd/10.2174/0115701808356442241221183358
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Supplementary material has the chemical structures of 169 marine xanthones (Fig. ); The active site gorge of the PDE5 protein (Fig. ); 2D interaction views of the 23 potential xanthones (ΔGestimated < -11 kcal/mol) interact with amino acid residues in the binding pocket of the PDE5 protein (Fig. ); RMSD of protein backbone in complexes with 21 potential xanthones compared to apo-protein and reference (Fig. ); RMSD of ligand in complexes with 21 potential xanthones compared to apo-protein and reference (Fig. ); Binding free energy of 23 potential compounds against PDE5 protein (Fig. ); HOMO and LUMO maps of quantum chemical calculation of 21 potential xanthones (Fig. ); MEP maps of quantum chemical calculation of hit compounds (Fig. ); Binding affinity of 169 studied xanthones with the PDE5 protein (Table ); Binding affinity and Amino acid residue interactions of the hit compounds from marine xanthones database against PDE5 (Table ); ADMET profiles of top 21 potential compounds (Table ). Supplementary material is available on the publisher's website along with the published article.

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  • Article Type:     Research Article
Keyword(s): erectile dysfunction; marine xanthones; molecular docking; molecular dynamics; phosphodiesterase-5 (PDE5); Xanthones

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