Scaffold identification and drug repurposing for finding potential Dengue envelope inhibitors through ligand-based pharmacophore model

Abstract

Most of the existing DENV entry inhibitors were discovered through structure-based, high-throughput screening techniques and optimization approaches by aiming β-OG pocket. However, the class of precise chemical scaffolds with superior antiviral activity targeting the early stages of virus infection that is considered to be beneficial in therapeutics and is still in process. In this study, ligand-based pharmacophore modeling using existing DENV entry inhibitors provided two best models, AADRR-2 and AAADR-2 (A- accepter, D- donor, R-ring) to screen public and DrugBank datasets. Further, approximately 36000 molecules were filtered using Zinc13 by employing the ideal validated models. Additionally, using β-OG binding pocket as target site, molecular docking experiments including induced-fit studies were conducted that provided further structurally divergent ligands. Moreover, the refined list of preferential hits were filtered out based on the best fitness score, binding energy and interaction paradigm, among them fused pyrimidine, hydrazone and biphenyl core comprising scaffolds were identified possessing profound interaction profile with key amino acid residues, ALA-50, GLN-200, PHE-193 and PHE-279 in 100 ns MD simulations. Additionally, the search for similar chemical fingerprints from DrugBank library was also carried out and Eltrombopag (Promacta/Revolade® prescribed in thrombocytopenia) was identified as a preferential β-OG pocket binder. The identified pyrazole-based hydrazone class of drug, Eltrombopag is in phase II clinical trials employed to treat dengue-mediated thrombocytopenia.

Communicated by Ramaswamy H. Sarma

Keywords:

• Dengue
• envelope
• pharmacophore
• dataset
• screening
• Eltrombopag

Acknowledgments

We thank CSIR-IICT for providing laboratory facility for carrying out this computational research work. SVS is thankful to CSIR fellowship (Project entitled “Discovery & pre-clinical development of anti-virals for COVID-19 and other diseases”, Project code: HCP-0041). Special thanks to Vinod Devaraji and team for their background support. IICT/Pubs./2022/316.

Disclosure statement

The authors report no conflict of interest.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.