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    • Currently the computational chemical biology has been applie

    2022-08-03

    Currently, the computational chemical biology has been applied in hepatitis B antiviral drug discovery research [18]. Tan et al. explored oxime ethers as HBV inhibitors by docking and screening [19]. Allen et al. clarified the resistance of HBV to the nucleoside drug lamivudine [20]. The results suggest that mutations in HBV polymerase allow for drug resistance to develop. Ma et al. used three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the anti-HBV activities of the arylpropenamide molecules [21]. A more reliable conclusion might be obtained when integrating MD simulation and 3D-QSAR methods. Tu et al. performed a study to the binding mechanism of HBV core protein to the HAPs analogue NVR-010-001-E2 by 3D-QSAR and MD simulation methods [22]. The results show that this compound can induce assembly of the HBV core wild-type and Y132A mutant proteins; the non-polar contribution and hydrogen bond interaction are the major driving force and Y132A mutation has little effect on the interaction between HAPs and HBV. Furthermore, HAPs derivatives with different scaffolds may have different binding modes with HBV core protein. Recently, as the inhibitors of HBV CGK733 receptor assembly, a novel series of tetrahydropyrrolo[1,2-c]pyrimidines derivatives were designed and synthesized [23]. These derivatives introduced fused ring around the dihydropyrimidine core based on HAPs (Bay41-4109 and GLS4). Hereinto, the highly efficacious compound 28a may serve as a promising starting point for further drug design. Comparing the structures of compounds NVR-010-001-E2 and 28a, the difference lies mainly in the morpholine part. The binding mechanism of NVR-010-001-E2 targeting on HBV capsid core protein has been revealed [22]. The latter also has good biological activity without morpholine structure and needs to be further explored at molecular level.
    Materials and methods
    Results and discussion
    Conclusion In the present study, several tetrahydropyrrolopyrimidines based on Bay41_4109 and GLS4 were explored using a combination of molecular modeling techniques including molecular docking, molecular dynamics simulations, binding energy calculations, per-residue free energy decomposition and 3D-QSAR. Gratifyingly, the binding free energy results obtained from MM/GBSA calculations exhibit a consistent order with the corresponding values of experimental activities and show that the hydrogen bond interaction, nonpolar interaction, polar interaction and π–π stacking interaction together play a stabilizing role in HBV core protein. Some vital residues Pro25, Thr33, Trp102, Ile105, Ile139, Leu140 from chain B and Val124, Thr128 from chain C have critical impacts on the inhibitors binding with HBV capsid protein. Thereinto, non-polar contributions of those residues are main driving force. More significantly, Trp102 stabilizes HBV protein conformations by providing hydrogen bond with the dihydropyrimidine of the inhibitors. Additionally, 3D-QSAR results further prove that the binding effects of substituents on the inhibition of HBV capsid protein. These mean that small methoxy and hydrophilic bulky groups such as sulphonamide are favorable to improve the binding affinity of inhibitor. And hydrophobic thiazole and electronegative groups such as F, Cl at corresponding position are useful to enhance activity. According to the analytical results, three new molecules were designed and N2 showed the highest docking score. Then the designed N2 was evaluated and analyzed by MD simulations and binding free energy calculations. In summary, we expect that these designed molecules could act as better inhibitors.
    Conflicts of interest
    Acknowledgement This work was supported by the National Natural Science Foundation of China (NSFC, no. 21275067).
    Introduction Hepatitis B virus (HBV) infection remains a serious public health problem all over the world. When HBV invades the human body, it enters the hepatocyte by means of binding to the receptor. Then, HBV DNA is transported into the nucleus of hepatocyte and converted to cccDNA under the action of host enzymes. The cccDNA is not easily degradable, (Le Mire et al., 2005) which is an important reason why chronic hepatitis B is difficult to cure. Currently available antiviral agents are effective to block the infection by free virus particles, but are still far from ideal to eliminate HBV since the drugs do not directly target cccDNA (Hoofnagle et al., 2007). Besides, the long-term antiviral treatment has led to the problem of drug-resistant strains. That is why it is crucial to understand the infection and pathogenesis mechanism of HBV.