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

Abstract

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.

A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

“…There are five putative HDACs in P. falciparum; PfHDAC1 (PF3D7_0925700) is the only class I HDAC representative in P. falciparum, while PfHDA1 (PF3D7_1472200) and PfHDA2 (PF3D7_1008000) belong to class II HDACs, and PfSir2a (PF3D7_1328800) and PfSir2b (PF3D7_1451400) are phylogenetically close to class III HDACs 47 . Several HDAC inhibitors with in vitro and in vivo antiplasmodial activity have been reported previously [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]37,38,[57][58][59][60][61] . For instance, WR301801 was discovered via chemical modification based on the structure of SAHA and can inhibit the growth of plasmodial at a low-nanomolar range in vitro, and the selectivity index is about 1000.…”

The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats

“…Eighteen mammalian HDACs have been identified so far [ 2 ], and have been subdivided into four different classes based on their homology with yeast HDACs. HDAC inhibitors (HDACi), such as the anticonvulsant drug valproic acid (VPA), have been identified as neoadjuvant to chemotherapy and radiotherapy [ 3 ]. The VPA-induced sensitization of tumor cells has been attributed to its effect on HDAC-dependent transcriptional repression and hyperacetylation of histones, which resulted in the differentiation of tumor cells and increased both apoptotic and non-apoptotic cell death [ 4 , 5 ].…”

PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum

“…In this study, we focus on the class I histone deacetylase PfHDAC1, which is a prime antimalarial target [22, 23] and is critical for parasite viability [19, 23, 34]. We identified that the enzymatic activity of PfHDAC1 is governed by its posttranslational modification (serine phosphorylation) status, which is similar to what is observed for higher eukaryotic HDACs [37].…”