Quantum biochemical analysis of the binding interactions between a potential inhibitory drug and the Ebola viral glycoprotein

Abstract

Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.

Communicated by Ramaswamy H. Sarma

Keywords:

• Ebola virus disease
• toremifene
• envelope glycoprotein
• interaction analysis
• DFT calculations
• molecular fractionation method with conjugate caps (MFCC) scheme

Acknowledgments

We would like to thank Brazilian Research Agencies CAPES and CNPq, and the Núcleo de Processamento de Alto Desempenho (NPAD) of the Universidade Federal do Rio Grande do Norte to allow us to access their computer facilities. The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/410/44

Disclosure statement

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

Author contributions

Conceptualization, J.M.d.R., D.M.d.O.C, S.C.E., J.I.N.O., and S.A; Formal analysis, J.M.d.R., JZT., G.d.L.M., and TA; Methodology, J.M.d.R., G.d.L.M., D.M.d.O.C., S.C.E., U.L.F., J.I.N.O., S.A.; Resource: K.S.B., D.d.S.J, and R.A.d. S; Investigations: D.d.S.J, R.A.d.S;, S.C.E., and J.I.N.O; Project Administration, U.L.F., TA, J.I.N.O.; and JZT; Supervision, J.I.N.O., U.L.F.; Validation, G.d.L.M., K.S.B., U.L.F., and S.A; Writing - original draft, J.M.d.R., D.M.d.O.C.; G.d.L.M., ., K.S.B., JZT., and S.C.E; Data curation: R.A.d.S., D.d.S.J, and T.A; Reviewing, and editing: G.d.L.M., D.M.d.O.C., and J.I.N.O.

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/410/44.