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A computational and laboratory approach for the investigation of interactions of peptide conjugated natural terpenes with EpHA2 receptor

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Abstract

Context

Ephrin type A receptor 2 (EphA2) is a well-known drug target for cancer treatment due to its overexpression in numerous types of cancers. Thus, it is crucial to determine the binding interactions of this receptor with both the ligand-binding domain (LBD) and the kinase-binding domain (KBD) through a targeted approach in order to modulate its activity. In this work, natural terpenes with inherent anticancer properties were conjugated with short peptides YSAYP and SWLAY that are known to bind to the LBD of EphA2 receptor. We examined the binding interactions of six terpenes (maslinic acid, levopimaric acid, quinopimaric acid, oleanolic, polyalthic, and hydroxybetulinic acid) conjugated to the above peptides with the ligand-binding domain (LBD) of EphA2 receptor computationally. Additionally, following the “target-hop** approach,” we also examined the interactions of the conjugates with the KBD. Our results indicated that most of the conjugates showed higher binding interactions with the EphA2 kinase domain compared to LBD. Furthermore, the binding affinities of the terpenes increased upon conjugating the peptides with the terpenes. In order to further investigate the specificity toward EphA2 kinase domain, we also examined the binding interactions of the terpenes conjugated to VPWXE (x = norleucine), as VPWXE has been shown to bind to other RTKs. Our results indicated that the terpenes conjugated to SWLAY in particular showed high efficacy toward binding to the KBD. We also designed conjugates where in the peptide portion and the terpenes were separated by a butyl (C4) group linker to examine if the binding interactions could be enhanced. Docking studies showed that the conjugates with linkers had enhanced binding with the LBD compared to those without linkers, though binding remained slightly higher without linkers toward the KBD. As a proof of concept, maslinate and oleanolate conjugates of each of the peptides were then tested with F98 tumor cells which are known to overexpress EphA2 receptor. Results indicated that the oleanolate-amido-SWLAY conjugates were efficacious in reducing the cell proliferation of the tumor cells and may be potentially developed and further studied for targeting tumor cells overexpressing the EphA2 receptor. To test if these conjugates could bind to the receptor and potentially function as kinase inhibitors, we conducted SPR analysis and ADP-Glo assay. Our results indicated that OA conjugate with SWLAY showed the highest inhibition.

Methods

Docking studies were carried out using AutoDock Vina, v.1.2.0; Molecular Dynamics and MMGBSA calculations were carried out through Schrodinger Software DESMOND.

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Data availability

Additional data available in supporting documents, and manuscript will be available on the faculty website.

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Acknowledgements

BG thanks the Clare Boothe Luce Foundation and Fordham University Research Grant for financial support of this work. BG also would like to thank Ms. Lucy Hart for her assistance with cell studies. IB thanks Fordham University research grants for financial support of this work.

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  1. Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA

    Beatriz G. Goncalves & Ipsita A. Banerjee

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  1. Beatriz G. Goncalves
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  2. Ipsita A. Banerjee
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Ipsita Banerjee was responsible for conception and design. Material preparation and data collection was performed by Beatriz Goncalves. The first draft of the manuscript was written by Beatriz Goncalves and both authors commented on previous versions of the manuscript. Beatriz Goncalves and Ipsita Banerjee were responsible for data analysis. Final manuscript was written and edited by Ipsita Banerjee.

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Correspondence to Ipsita A. Banerjee.

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Goncalves, B.G., Banerjee, I.A. A computational and laboratory approach for the investigation of interactions of peptide conjugated natural terpenes with EpHA2 receptor. J Mol Model 29, 204 (2023). https://doi.org/10.1007/s00894-023-05596-3

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