Structure-Based Molecular Screening and Simulation Approaches To Inhibit Marburg Virus VP35 Protein Using Medicinal Phytocompounds for Restoring Host Immune Response

Abstract

Purpose

The Marburg virus (MARV) is notable for its high mortality rate and potential for widespread transmission. The VP35 protein of MARV is a critical target for therapeutic intervention as it plays a key role in suppressing the host’s immune response, contributing to the virus’s pathogenicity. VP35 binds to viral double-stranded RNA (dsRNA), triggering immunosuppressive actions such as inhibiting the type I interferon (IFN) response, preventing the activation of interferon regulatory factor 3 (IRF-3), and stifling RNA silencing mechanisms.

Methods

we used structure-based drug design, molecular simulations, and binding free energy approaches, to identify potent phytocompounds from various natural product databases that could inhibit the MARV VP35 protein.

Results

Through virtual screening of African natural compounds databases against the RNA binding domain of VP35, we identified five potent compounds such as EA/NA-3,083,880 (-6.291 kcal/mol), EA/NA-15,071,544 (-6.062 kcal/mol), EA/NA-5,242,842-VP35 (-5.606 kcal/mol), EA/NA-1057 (-5.247 kcal/mol), and SA-5,281,343 (-5.083 kcal/mol) based on their high docking scores and binding affinities. Further validation through molecular dynamics simulation and dissociation constant analysis confirmed the strong binding affinities of these compounds with the VP35 protein of the MARV. Moreover, the binding free energies for EA/NA-3,083,880, EA/NA-15,071,544, EA/NA-5,242,842-VP35, EA/NA-1057, and SA-5,281,343 were recorded as -32.07 ± 0.21 kcal/mol, -38.44 ± 0.45 kcal/mol, -23.95 ± 0.24 kcal/mol, -47.55 ± 0.22 kcal/mol, and − 26.43 ± 0.22 kcal/mol, respectively, confirming their strong binding affinities with VP35. The chosen compounds demonstrated exceptional water solubility and intestinal absorption, without causing skin sensitization or hepatotoxicity. They also adhered to Lipinski’s rules.

Conclusion

The strong binding affinities and favourable pharmacokinetic profiles indicate that these compounds are prime candidates for further in-depth research, both in-vitro and in-vivo, with potential for development as therapeutic agents against the MARV.