Synergistic effects in the designs of neuraminidase ligands: Analysis from docking and molecular dynamics studies

Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, PR China.
Journal of Theoretical Biology (Impact Factor: 2.12). 12/2010; 267(3):363-74. DOI: 10.1016/j.jtbi.2010.08.029
Source: PubMed


Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC(50) value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs.

10 Reads
  • Source
    • "Geometry and partial atomic charges of the tripeptide Met-Ala-Ser were conducted throughout the Discover 3.0 module by applying the BFGS algorithm [31] with a convergence criterion of 0.01 kcal·mol−1·Å−1. As demonstrated by previous results [32,33], the docking simulations were performed to explore and understand the interactions of PtrPDF1A and PtrPDF1B with the tripeptide Met-Ala-Ser using the general protocols in the InsightII 2005 software packages [32,34]. The interaction energies of the substrate with proteins were calculated by the Docking module [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peptide deformylases (PDF) behave as monomeric metal cation hydrolases for the removal of the N-formyl group (Fo). This is an essential step in the N-terminal Met excision (NME) that occurs in these proteins from eukaryotic mitochondria or chloroplasts. Although PDFs have been identified and their structure and function have been characterized in several herbaceous species, it remains as yet unexplored in poplar. Here, we report on the first identification of two genes (PtrPDF1A and PtrPDF1B) respectively encoding two putative PDF polypeptides in Populus trichocarpa by genome-wide investigation. One of them (XP_002300047.1) encoded by PtrPDF1B (XM_002300011.1) was truncated, and then revised into a complete sequence based on its ESTs support with high confidence. We document that the two PDF1s of Populus are evolutionarily divergent, likely as a result of independent duplicated events. Furthermore, in silico simulations demonstrated that PtrPDF1A and PtrPDF1B should act as similar PDF catalytic activities to their corresponding PDF orthologs in Arabidopsis. This result would be value of for further assessment of their biological activities in poplar, and further experiments are now required to confirm them.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
  • Source
    • "Geometry and partial atomic charges of the substrate were conducted using the Discover 3.0 module by applying the BFGS algorithm (Head and Zerner, 1985) with a convergence criterion of 0.01 kcal mol -1 Å -1 . Previous literatures revealed that (Yang et al., 2009; Yang et al., 2010b; Yang et al., 2010a), the docking and molecular dynamics (MD) simulations were performed to explore and understand the interactions between peptide-bougies and poplar CK2α proteins, by the general protocols in the InsightII 2005 software packages (Affinity User Guide, 2005; Yang et al., 2009, 2010a, a). The MD trajectories were generated using a 1.0 fs time step for a total of 5000 ps, saved at 5.0-ps intervals. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Casein kinase 2 (CK2) is a ubiquitous serine-threonine protein kinase, which of specific substrates are involved in the regulation of several vital physiological processes in plants. Detailed studies of CK2 have focused on the herbaceous species of Arabidopsis, maize, however, it has remained largely unexplored in woody trees. In this study, we identified the four genes encoding CK2α subunits in a search for Populus genome. Reorganization of CK2α genes in Populus genome showed that its multiple copies are resulted from segmental duplication and tandem duplication events. Phylogenetic and in silico expression analysis indicated that, the divergence was present among poplar CK2α genes, dividing into type I and type II, and each type represented by relatively consistent expression profile. Further docking and molecular dynamic simulations revealed that the poplar CK2α specifically recognize the special pentapeptides (XES/T*DD) of natural substrates and then introduce the phosphorylation of C-terminal region of poplar P-protein. This study will provide the insight into the understanding of interacting mechanism of poplar CK2α with their natural substrates, and be of valuable resource for further assessment of the function of phosphorylation of P-protein in woody plants.
    Full-text · Article · Nov 2011 · African journal of microbiology research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH(3) (+)) and C-terminus (COO(-)) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N-terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.
    Full-text · Article · Dec 2010 · International Journal of Molecular Sciences
Show more