Article

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: 2.35). 12/2010; 267(3):363-74. DOI: 10.1016/j.jtbi.2010.08.029
Source: PubMed

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.

0 Bookmarks
 · 
75 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The antitumor bioactivities of linobiflavonoid were studied through evaluating its in vitro cytotoxicity against several cell lines (A549, H1975, SMMC-7721, HEP-2 and Vero cells), with the aid of 3-(4,5)-dimethylthiazoly1)-3,5-diphenytetrazolium bromide (MTT) assay. It was found that linobiflavonoid shows more notable inhibiting activity against A549 cells, with IC50 value of 4.67 μM. Furthermore, western blot analysis revealed that linobiflavonoid is able to increase the expression of β-tubulin, whereas not α-tubulin. In virtuale simulations indicated that linobiflavonoid specifically interacts with the binding pocket which is located at the top of β-tubulin, due to the presence of strong hydrophobic effects between the core templates and the hydrophobic surface of the tubulin protein (TB) binding site. The binding energy (E inter ) was calculated to be -140.47 kcal/mol. Results above suggest that linobiflavonoid possesses anti-A549 properties relating to β-tubulin depolymerization inhibition.
    Molecular Biology Reports 09/2013; · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.
    Current Medicinal Chemistry 03/2013; · 3.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A systematic study has been performed on neuraminidase (NA) mutations and NA-inhibitor docked complexes, with the aim to understand protein-ligand interactions and design broad-spectrum antiviral drugs with minimal resistances. The catalytic D151 residue is likely to mutate while others are relatively conserved. The NA active-site conformations are altered by mutations, but more alterations do not necessarily result in larger deviations to the binding properties. The effects of all related mutations have been discussed; e.g., for the arginine triad (R118, R292 and R371), it is found that residue R118 plays the most significant role during ligand binding. Generally, the calculated binding free energies agree well with the experimental observations. Susceptibility of influenza virus to NA inhibitors can be reinforced by some mutations; e.g., the binding free energies of ligands with N2 subtype increase from -18.0 to -42.1 kcal mol(-1) by the E119D mutation. Mutations of the various NA subtypes often cause similar conformational and binding changes, explaining the occurrence of cross resistances; nonetheless, differences can be detected in some cases that correspond to subtype-specific resistances. For all NA subtypes, the electrostatic contributions are the major driving force for ligand binding and largely responsible for the binding differences between the wild-type and mutated NA proteins.
    Journal of Computer-Aided Molecular Design 11/2013; · 3.17 Impact Factor