Marine phycocompound screening reveals a potential source of novel senotherapeutics

Abstract

Cells undergo a controlled and systematic cycle of growth, replication and death. However, the integrity of this process gradually declines, leading to accumulation of senescent cells, a major hallmark of biological ageing. Dietary algae, particularly marine algae, have been long reported to exert anti-ageing benefits as cosmeceuticals and nutraceuticals with limited understanding of the molecular mechanisms underlying their activity. In this study, we have incorporated 1,202 previously reported bioactive small phycocompounds and subjected them to cheminformatic queries to assess these interactions. In-silico ADMET, 2-phase docking, metabolic pathway interaction and molecular dynamics simulations reveal multiple marine phycocompounds to have safe and effective senolytic potentials. We employed a novel deep convolutional neural network driven screening approach to identify (2R*, 3S*, 6R*, 7S*, 10R*, 13R*)-7,13-Dihydroxy-2,6-cyclo-1(9),14-xenicadiene-18,19-dial derived from Dilophus Fasciola, Laurendecumenyne A from Laurencia decumbens and 4-Bromo-3-ethyl-9-[(2E)-2-penten-4-yn-1-yl]-2,8-dioxabicyclo[5.2.1]decan-6-ol from Laurencia sp. to be potent inhibitors of multiple target senescent-cell anti-apoptotic pathway proteins. We simulated the best overall target inhibitors, specific protein inhibitors and molecular pathway regulators with each target protein and found stable interactions with minimum deviations (mean RMSD = 0.17 ± 0.01 nm) and gyrations (mean Rg = 1.64 ± 0.16 nm) of the simulated protein-compound complexes. Finally, molecular mechanics calculation suggests potent (mean ΔG = −69.56 ± 27.19 kCal/mol) and frequent hydrophobic interactions between the top performing marine phycocompounds and target proteins.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-ageing
• senolytics
• marine algae
• cheminformatics
• drug discovery

Acknowledgements

We are grateful to Dr. G Dicky John Davis from Sri Ramachandra University, India and Dr. A. Hannah Rachel Vasanthi from Pondicherry University, India for their technical and intellectual assistance throughout the duration of the project.

Declaration of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

R Salekeen, PR Shaha and J Barua designed the methodology, conducted experimentation and formal analysis, prepared the data and visuals; R Salekeen wrote the original draft; MM Billah and ME Islam reviewed and edited the manuscript; KMD Islam and SMM Rahman conceptualized and supervised the project. All authors discussed the results and agreed on the final manuscript.