Structure-based virtual screening of influenza virus RNA polymerase inhibitors from natural compounds: Molecular dynamics simulation and MM-GBSA calculation. (April 2020)

• Record Type: Journal Article
• Authors: Jin, Zhe; Wang, Ying; Yu, Xiao-Fei; Tan, Qi-Qi; Liang, Shi-Shao; Li, Tai; Zhang, Hong; Shaw, Pang-Chui; Wang, Jian; Hu, Chun
• Is Part Of: Computational biology and chemistry. Volume 85(2020)
• Publication Date: 2020-04
• Subjects: M2 protein Matrix protein 2 -- RNA ribonucleic acid -- PA polymerase acidic protein -- PB1 polymerase basic protein 1 -- ADMET absorption distribution, metabolism, excretion, and toxicity -- HBA hydrogen-bond acceptor -- HBD hydrogen-bond donor -- TPSA topological polar surface area -- IAV influenza A virus -- IBV influenza B virus -- ICV influenza C virus -- PSE ethanolic extract of Peperomia sui -- NP nucleoprotein -- TGBG 13, 4, 6-tetra-O-galloyl-β-D-glucopyranoside -- PB2 polymerase basic protein 2 -- FDA food and drug administration U.S -- mRNA messenger ribonucleic acid -- RCSB research collaboratory for structural bioinformatics U.S -- PDB protein data bank -- PAC C-terminal region of PA -- PB1N N-terminal region of PB1 -- SP standard precision -- MW molecular weight -- Fraction Csp3 fraction of carbons in the sp3 hybridization -- GI gastrointestinal -- BBB blood brain barrier -- P-gp P-glycoprotein -- PSA polar surface area -- PPB plasma protein binding -- MD Molecular dynamics -- RMSD root mean square deviation -- rGyr radius of gyration -- intraHB intramolecular hydrogen bond -- MolSA molecular surface area -- SASA solvent accessible surface area -- VS virtual screening -- MM-GBSA molecular mechanics / generalized born surface area; Influenza virus -- Protein-protein interaction inhibitor -- Virtual screening -- Drug likeness -- Molecular dynamics simulations; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2020.107241
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Structure-based virtual screening was performed to discover influenza virus polymerase inhibitors. Three natural compounds were identified to potentially block the interaction of PA-PB1 subunit of influenza virus polymerase. The three compounds showed less or no hepatotoxicity, nor plasma protein biding (PPB) ability. The stability of the complexes of PA-hits was validated through molecular dynamics (MD) simulation. Four key residues of PA subunit participating in the interactions were revealed. Abstract: The resistances of matrix protein 2 (M2) protein inhibitors and neuraminidase inhibitors for influenza virus have attracted much attention and there is an urgent need for new drug. The antiviral drugs that selectively act on RNA polymerase are less prone to resistance and possess fewer side effects on the patient. Therefore, there is increased interest in screening compounds that can inhibit influenza virus RNA polymerase. Three natural compounds were found by using molecular docking-based virtual screening, which could bind tightly within the polymerase acidic protein-polymerase basic protein 1 (PA-PB1) subunit of influenza virus polymerase. Firstly, their drug likeness properties were evaluated, which showed that the hepatotoxicity values of all the three compounds indicating they had less or no hepatotoxicity, and did not have the plasma protein biding (PPB) ability, the three compounds needed to be modified in some aspects, like bulky molecular size. The stability of the complexes of PA-hits was validated through molecular dynamics (MD) simulation, revealing compound 2 could form more stable complex with PA subunit. The torsional conformations of each rotatable bond of the ligands in PA subunit were also monitored, to investigate variation in the ligand properties during the simulation, compound 3 had fewer rotatable bonds, indicating that the molecule had stronger rigidity. The bar charts of protein–ligand contacts and contacts over the course of trajectory showed that four key residues (Glu623, Lys643, Asn703 and Trp706) of PA subunit that participated in hydrogen-bond, water bridge and hydrophobic interactions with the hit compounds. Finally, the binding free energy and contributed energies were calculated by using MM-GBSA method. Out of the three compounds, compound 1 showed the lowest total binding free energy. Among all the interactions, the contribution of the covalent binding and the van der Waals energy were more than other items, compound 1 formed more stable hydrogen bonds with the residues of PA subunit binding pocket. This study smoothed the path for the development of novel lead compounds with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of influenza, which provided a good basis for further research on novel and effective influenza virus PA-PB1 interaction inhibitors.