In-silico screening and identification of potential drug-like compounds for dengue-associated thrombocytopenia from Carica papaya leaf extracts

Abstract

Dengue virus is a mosquito-borne pathogen that causes a variety of illnesses ranging from mild fever to severe and fatal dengue haemorrhagic fever or dengue shock syndrome. One of the major clinical manifestations of severe dengue infection is thrombocytopenia. The dengue non-structural protein 1 (NS1) is the primary protein that stimulates immune cells via toll-like receptor 4 (TLR4), induces platelets, and promotes aggregation, which could result in thrombocytopenia. The leaf extracts of Carica papaya seem to have therapeutic benefits in managing thrombocytopenia associated with dengue. The present study focuses on understanding the underlying mechanism of the use of papaya leaf extracts in treating thrombocytopenia. We have identified 124 phytocompounds that are present in the papaya leaf extract. The pharmacokinetics, molecular docking, binding free energy calculations, and molecular dynamic simulations were performed to investigate the drug-like properties, binding affinities, and interaction of phytocompounds with NS1 protein as well as the interactions of NS1 with TLR4. Three phytocompounds were found to bind with the ASN130, a crucial amino acid residue in the active site of the NS1 protein. Thus, we conclude that Rutin, Myricetin 3-rhamnoside, or Kaempferol 3-(2''-rhamnosylrutinoside) may serve as promising molecules by ameliorating thrombocytopenia in dengue-infected patients by interfering the interaction of NS1 with TLR4. These molecules can serve as drugs in the management of dengue-associated thrombocytopenia after verifying their effectiveness and assessing the drug potency, through additional in-vitro assays.

Communicated by Ramaswamy H. Sarma

Keywords:

• Dengue virus
• non-structural protein 1
• carica papaya
• phytocompounds
• thrombocytopenia

CRediT authorship statement

AR developed the original hypothesis for the work. AR and BB developed the computational workflow and wrote the initial draft of the manuscript. BB, AJK, and DK did the Molecular docking and dynamics studies. SS, AL, and RR critically evaluated the manuscript and ensured that the study’s scientific aspect was rationally valid. All authors read, edited, and approved the final manuscript.

List of 124 phytocompounds of Carica papaya leaf extracts obtained from a thorough literature survey and their respective PubChem CID are listed in Supplementary Table 1.

The drug-likeliness properties of 124 phytocompounds from papaya leaf extract were evaluated using DruLiTo software given in Supplementary Table 2.

Acknowledgements

We thank the Yenepoya (Deemed to be University) for the facility support to the Centre for Integrative Omics Data Science (CIODS). This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Amjesh Revikumar is a recipient of a national post-doctoral fellowship [PDF/2017/001652] and Rajesh Raju is a recipient of the Young Scientist Award [YSS/2014/000607] from the Science and Engineering Research Board, Department of Science and Technology (DST), Government of India.