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Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity

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Abstract

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI–diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI–diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI–diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein–protein interaction of the potential targets of esculetin and phloretin against AKI–diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI–diabetes comorbidity. We obtained 6341 targets for AKI–diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI–diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin’s 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI–diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI–diabetes comorbidity.

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Abbreviations

AKI :

Acute kidney injury

ACHE :

Acetylcholinesterase

AKR1B1 :

Aldo–keto reductase family 1, member B1

APP :

Amyloid precursor protein

ARG :

Arginine

ASN :

Asparagine

ASP :

Aspartic acid

CA3 :

Carbonic anhydrase 3

CA2 :

Carbonic anhydrase 2

CCNE1 :

Cyclin E1

CDK1 :

Cyclin-dependent kinase 1

CDK5R1 :

Cyclin-dependent kinase 5 regulatory subunit 1

CYS :

Cysteine

DAO :

D-amino acid oxidase

ESR1 :

Oestrogen receptor 1

GLN :

Glutamine

GLU :

Glutamic acid

HDAC6 :

Histone deacetylase 6

HIE :

Histidine

ILE :

Isoleucine

LEU :

Leucine

LYS :

Lysine

MAOA :

Monoamine oxidase A

MAOB :

Monoamine oxidase B

MAPK14 :

Mitogen-activated protein kinase 14

PHE :

Phenylalanine

PLK1 :

Polo-like kinase 1

PRKN :

Parkin RBR E3 Ubiquitin Protein Ligase

PRO :

Proline

SER :

Serine

THR :

Threonine

TRP :

Tryptophan

TYR :

Tyrosine

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Acknowledgements

ABG sincerely acknowledges the financial support provided by the Birla Institute of Technology and Science, Pilani, Pilani Campus, for carrying out this work.

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No funding was received for conducting this study.

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Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, 333031, Rajasthan, India

    Neha Dagar, Hemant R. Jadhav & Anil Bhanudas Gaikwad

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  1. Neha Dagar
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  2. Hemant R. Jadhav
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  3. Anil Bhanudas Gaikwad
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Contributions

N.D. was involved in conceptualization, writing—original draft preparation, methodology, investigation, data analysis. H.R.J. helped in writing—review & editing of the manuscript. A.B.G. conceptualised and designed the experiments, writing—review & editing of the manuscript, supervision. All authors have approved the final manuscript draft for publication.

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Correspondence to Anil Bhanudas Gaikwad.

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Dagar, N., Jadhav, H.R. & Gaikwad, A.B. Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10829-5

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