Elbadawi Mohamed A Abdallah, Awadalla Mohamed Khalid Alhaj, Hamid Muzamil Mahdi Abdel, Mohamed Magdi Awadalla, Awad Talal Ahmed
Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan.
College of Pharmacy, University of Hail, Hail 81451, Saudi Arabia.
Int J Mol Sci. 2015 Feb 11;16(2):3915-31. doi: 10.3390/ijms16023915.
A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.
基于序列同源性最高的模板人类组蛋白去乙酰化酶2的结构，构建了一种新的恶性疟原虫组蛋白去乙酰化酶1（PfHDAC1）同源模型。对生成的模型进行了仔细评估，包括立体化学准确性、折叠正确性和整体结构质量。所有评估结果均可接受且一致。对接一组异羟肟酸组蛋白去乙酰化酶抑制剂和丙戊酸，所显示的结合构象与抑制剂结合的组蛋白去乙酰化酶解析结构相互作用非常吻合。对接亲和力dG分数与现有的实验结合亲和力一致。此外，通过运行5纳秒的分子动力学模拟研究了酶-配体复合物的稳定性和可靠性。对模拟轨迹的深入分析表明，酶-配体复合物在模拟期间是稳定的。有趣的是，对接的异羟肟酸抑制剂的计算理论结合能表明，该模型能够区分强抑制剂和弱抑制剂，并且与文献报道的实验亲和力非常吻合。该模型和对接方法可用于筛选PfHDAC1抑制剂的虚拟文库，因为对接分数已根据实验结合亲和力对配体进行了排序。丙戊酸的计算理论结合能表明它可能抑制PfHDAC1。
