Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach

International Journal of Molecular Sciences

Mohamed A. Abdallah Elbadawi²  Mohamed Khalid Alhaj Awadalla³  Muzamil Mahdi Abdel Hamid¹  Magdi Awadalla Mohamed⁴  Talal Ahmed Awad⁵ 

[1] Department of Parasitology and Medical Entomology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan; E-Mail:;Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan; E-Mail:;College of Pharmacy, University of Hail, Hail 81451, Saudi Arabia;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan; E-Mail:;Medicinal and Aromatic Plants Research Institute, National Centre of Research, Khartoum 11111 Sudan; E-Mail:

关键词: PfHDAC1;    malaria;    valproic acid;    histone deacetylase inhibitor;    homology model;    docking;    molecular dynamics;    binding energy;   

DOI  :  10.3390/ijms16023915

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.