Synergistic effects in the designs of neuraminidase ligands: Analysis from docking and molecular dynamics studies
ABSTRACT 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.
- SourceAvailable from: Chang-Cai Liu
African journal of microbiology research 01/2011; 5(27):4850-4858. · 0.54 Impact Factor
- "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. "
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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.International Journal of Molecular Sciences 12/2010; 11(12):4932-51. DOI:10.3390/ijms11124932 · 2.34 Impact Factor
- African journal of microbiology research 11/2011; 5(27). DOI:10.5897/AJMR11.783 · 0.54 Impact Factor