Journal Article

Exploration of African natural products as VP35 inhibitors to combat Marburg virus infection: Molecular docking, molecular dynamics, and quantum mechanical computations

Abdelrahman, Alaa H. M., El-Tayeb, Mohamed A., Mekhemer, Gamal A. H., Sidhom, Peter A., Ibrahim, Mahmoud A. A., Khan, Shahzeb

2025

Overview

Marburg virus (MBV) is a highly lethal filovirus responsible for hemorrhagic fever with case fatality rates of up to 88%. MBV was first recognized in 1967 during simultaneous outbreaks in Marburg and Frankfurt, Germany, and Belgrade, then part of Yugoslavia (now Serbia), following exposure to infected African green monkeys imported from Uganda. Currently, no approved treatment exists for MBV infection. The viral protein (VP35) plays a critical role in viral replication, transcription, and nucleocapsid assembly, making it a promising antiviral target. Consequently, obstructing the function of VP35 offers a potential strategy for combating MBV. Herein, the African Natural Products (ANP) database, which encompasses over 6,500 compounds, was subjected to virtual screening against VP35 employing docking computations. For inhibitors exhibiting a docking score <−8.0 kcal/mol against VP35, molecular dynamics simulations (MDS) were conducted, along with binding energy assessment utilizing the MM/GBSA approach. Upon the MM/GBSA//250 ns MDS, ANPDB6426, ANPDB5109, and ANPDB6357 demonstrated promising binding affinities toward the VP35, with Δ G binding values of −37.9, −34.6, and −34.2 kcal/mol, respectively. The post-MD analyses demonstrated that all three ANPs remained remarkably stable within the VP35 binding pocket over the full 250 ns MDS. Furthermore, the identified ANPs unveiled favorable oral bioavailability, pharmacokinetic, and safety profiles. Density functional theory calculations further supported the chemical reactivity of the identified ANPs. Compared to galidesivir and favipiravir, reference inhibitors, the estimated MM/GBSA binding energies of the identified ANPs with VP35 were about two times lower than galidesivir and favipiravir. These results highlighted the efficacy of computational methods in recognizing putative VP35 inhibitors, providing promising avenues for additional experimental research and prospective curative advancement toward MBV.

• Publisher: Public Library of Science,PLOS,Public Library of Science (PLoS)
• Subject: Animals / Antiviral agents / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Binding energy / Bioavailability / Biological Products - chemistry / Biological Products - pharmacology / Biological Products - therapeutic use / Biology and Life Sciences / Cell cycle / Chemical reactions / Computer and Information Sciences / Density functional theory / Density functionals / Distribution / Ebola virus / Energy / Engineering and Technology / Experimental research / Force and energy / Health aspects / Hemorrhagic fever / Humans / Infection / Inhibitors / Marburg virus disease / Marburg Virus Disease - drug therapy / Marburg Virus Disease - virology / Marburgvirus - drug effects / Medicine and Health Sciences / Molecular docking / Molecular Docking Simulation / Molecular dynamics / Molecular Dynamics Simulation / Morphine / Natural products / Nucleocapsids / Pharmacokinetics / Physical Sciences / Prevention / Proteins / Quantum mechanics / Research and Analysis Methods / Risk factors / RNA polymerase / Testing / Viral diseases / Viral proteins / Viral Regulatory and Accessory Proteins - antagonists & inhibitors / Viral Regulatory and Accessory Proteins - chemistry / Viral Regulatory and Accessory Proteins - metabolism / Viruses