Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach
"> Figure 1
<p>Two-dimensional structures of the ligands used in docking work. (<b>a</b>) Trichostatin A (TSA); (<b>b</b>) suberoylanilide hydroxamic acid (SAHA); (<b>c</b>) suberoyl bis-hydroxamic acid (SBHA); and (<b>d</b>) valproic acid.</p> "> Figure 2
<p>Cartoon representation of homologues superposition. Human histone deacetylase 2 (HDAC2) in blue, <span class="html-italic">Plasmodium falciparum</span> histone deacetylase1 (<span class="html-italic">Pf</span>HDAC1) in green and zinc in yellow.</p> "> Figure 3
<p>Verify3D plot of the <span class="html-italic">Plasmodium falciparum</span> histone deacetylase1 <span class="html-italic">Pf</span>HDAC1 homology model.</p> "> Figure 4
<p>Protein Structure Assessment server (ProSA-web) result of the <span class="html-italic">Plasmodium falciparum</span> histone deacetylase1 <span class="html-italic">Pf</span>HDAC1 homology model; the black dot represents the model <span class="html-italic">z</span>-score.</p> "> Figure 5
<p><span class="html-italic">Plasmodium falciparum</span> histone deacetylase1 (<span class="html-italic">Pf</span>HDAC1) active site. (<b>a</b>) Gaussian contour of the <span class="html-italic">Pf</span>HDAC1 model active site (pink represents hydrogen bonding; green represents hydrophobic contact residues; blue represents mild polar amino acids); and (<b>b</b>) key residues of the model active site.</p> "> Figure 6
<p><span class="html-italic">Pf</span>HDAC1 model-ligand interactions. (<b>a</b>) TSA; (<b>b</b>) SAHA; and (<b>c</b>) SBHA. Bond distances are shown in angstroms.</p> "> Figure 7
<p>Valproic acid-<span class="html-italic">Pf</span>HDAC1 complex interactions.</p> "> Figure 8
<p>Root-mean-square deviation (RMSD) of Cα atoms of enzyme-ligand complexes <span class="html-italic">versus</span> time.</p> "> Figure 9
<p>Potential energies (kcal·mol<sup>−1</sup>) of <span class="html-italic">Plasmodium falciparum</span> histone deacetylase1 ligand complexes during molecular dynamics simulation.</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. Model Building and Refinement
2.2. Model Quality
2.3. Plasmodium Falciparum Histone Deacetylase1 Model
2.4. Docking
2.4.1. Hydroxamic Acid Inhibitor-PfHDAC1 Complexes
Ligand | IC50 (µM) a | Score | Binding Energy (kcal·mol−1) | |
---|---|---|---|---|
CQ b Resistant | CQ b Sensitive | |||
SAHA | 1.78 | 0.94 | −5.15 | 280.81 |
SBHA | 0.8 | 1.3 | −6.52 | 281.92 |
TSA | 0.008 | 0.11 | −6.92 | 308.54 |
Valproic acid | N.A. c | N.A. c | −5.13 | 219.67 |
2.4.2. Valproic Acid-PfHDAC1 Complex
2.5. Molecular Dynamics Simulations
2.6. Theoretical Binding Energies
3. Materials and Methods
3.1. Homology Modeling
3.2. Model Refinement
3.3. Model Quality Validation
3.4. Ligands Preparation
3.5. Docking
3.6. Molecular Dynamics Simulation
3.7. Ligand-Enzyme Complex Theoretical Binding Energy Calculation
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Elbadawi, M.A.A.; Awadalla, M.K.A.; Hamid, M.M.A.; Mohamed, M.A.; Awad, T.A. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach. Int. J. Mol. Sci. 2015, 16, 3915-3931. https://doi.org/10.3390/ijms16023915
Elbadawi MAA, Awadalla MKA, Hamid MMA, Mohamed MA, Awad TA. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach. International Journal of Molecular Sciences. 2015; 16(2):3915-3931. https://doi.org/10.3390/ijms16023915
Chicago/Turabian StyleElbadawi, Mohamed A. Abdallah, Mohamed Khalid Alhaj Awadalla, Muzamil Mahdi Abdel Hamid, Magdi Awadalla Mohamed, and Talal Ahmed Awad. 2015. "Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach" International Journal of Molecular Sciences 16, no. 2: 3915-3931. https://doi.org/10.3390/ijms16023915
APA StyleElbadawi, M. A. A., Awadalla, M. K. A., Hamid, M. M. A., Mohamed, M. A., & Awad, T. A. (2015). Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach. International Journal of Molecular Sciences, 16(2), 3915-3931. https://doi.org/10.3390/ijms16023915