Dengue virus, an arbovirus, leads to millions of infections every year ultimately leading to a high rate of mortality. Highly effective and specific therapeutic option is not available till date to combat viral infection. One of the first stages in the virus lifecycle encompasses the viral entry into the host cell which is mediated by the interaction between heparan sulphate and the Dengue virus envelope protein in turn leading to the interaction between the envelope protein receptor binding domain and host cell receptors. The heparan sulphate binding site on the envelope protein was established using literature survey and the result validated using ColDock simulations. We have performed virtual screening against the heparan sulphate binding site using DrugBank database and short-listed probable inhibitors based on binding energy calculation following Molecular Dynamics (MD) simulations in this study. Two compounds (PubChem IDS 448062 and 656615) were selected for further analyses on which RAMD simulations were performed to quantitate the binding stability of both the molecules in the protein binding pocket which ultimately led to the selection of ZK-806450 molecule as the final selected compound. Competitive binding MD simulation against dengue virus envelope protein was performed for this molecule and heparan sulphate in order to ascertain the efficiency of binding of this molecule to the dengue virus envelope protein in the presence of its natural ligand molecule and found that this molecule has a higher affinity for the dengue virus envelope protein GAG binding site than heparan sulphate. This study may help in the use of this inhibitor molecule to combat dengue virus infection in foreseeable future and open a new avenue for drug repurposing methodology using competitive binding MD simulation.

2005-07-01·European Journal of Medicinal Chemistry1区 · 医学

Ligand-based assessment of factor Xa binding site flexibility via elaborate pharmacophore exploration and genetic algorithm-based QSAR modeling

1区 · 医学

Article

作者: Dhia D. Zaki ; Mutasem O. Taha ; Amjad M. Qandil ; Murad A. AlDamen

The flexibility of activated factor X (fXa) binding site was assessed employing ligand-based pharmacophor modeling combined with genetic algorithm (GA)-based QSAR modeling. Four training subsets of wide structural diversity were selected from a total of 199 direct fXa inhibitors and were employed to generate different fXa pharmacophoric hypotheses using CATALYST software over two subsequent stages. In the first stage, high quality binding models (hypotheses) were identified. However, in the second stage, these models were refined by applying variable feature weight analysis to assess the relative significance of their features in the ligand-target affinity. The binding models were validated according to their coverage (capacity as a three-dimensional (3D) database search queries) and predictive potential as three-dimensional quantitative structure-activity relationship (3D-QSAR) models. Subsequently, GA and multiple linear regression (MLR) analysis were employed to construct different QSAR models from high quality pharmacophores and explore the statistical significance of combination models in explaining bioactivity variations across 199 fXa inhibitors. Three orthogonal pharmacophoric models emerged in the optimal QSAR equation suggesting they represent three binding modes accessible to ligands in the binding pocket within fXa.

2003-01-01·Journal of Medicinal Chemistry1区 · 医学

Human Factor Xa Bound Amidine Inhibitor Conformation by Double Rotational-Echo Double Resonance Nuclear Magnetic Resonance and Molecular Dynamics Simulations

1区 · 医学

Article

作者: McCarrick, Margaret A. ; Arnaiz, Damian ; Poliks, Barbara ; Guilford, William J. ; O'Connor, Robert D. ; McDowell, Lynda M. ; Dallas, Jerry L. ; Studelska, Daniel R. ; Schaefer, Jacob ; Adler, Marc ; Light, David R.

Double rotational-echo double resonance (double REDOR) NMR was used to investigate the conformation of a (13)C-, (15)N-, and (19)F-labeled inhibitor (Berlex Biosciences compound no. ZK-806299) bound to human factor Xa. Conformationally dependent carbon-fluorine dipolar couplings were measured by (13)C[(19)F] REDOR. Natural abundance carbon signals in the full-echo spectra were removed by (13)C[(15)N] REDOR. Major and minor binding modes were suggested by the NMR data, but only the former had adequate signal to noise for distance determinations. Molecular dynamics simulations restrained by double-REDOR-determined intramolecular (13)C-(19)F distances revealed two models for the dominant binding mode that are consistent with the NMR data. We conclude that ZK-806299 binds similarly to both FXa. Moreover, it appears to bind to FXa in a fashion previously demonstrated for ZK-807834, a more selective FXa inhibitor.

100 项与 ZK-806299 相关的药物交易

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