{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:16:28Z","timestamp":1780334188373,"version":"3.54.1"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2015,2,11]],"date-time":"2015-02-11T00:00:00Z","timestamp":1423612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms16023915","type":"journal-article","created":{"date-parts":[[2015,2,11]],"date-time":"2015-02-11T09:52:16Z","timestamp":1423648336000},"page":"3915-3931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Valproic Acid as a Potential Inhibitor of  Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1):  An in Silico Approach"],"prefix":"10.3390","volume":"16","author":[{"given":"Mohamed","family":"Elbadawi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum 11111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Awadalla","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Hail, Hail 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muzamil","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Medical Entomology, Institute of Endemic Diseases,  University of Khartoum, Khartoum 11111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdi","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Khartoum,  Khartoum 11111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talal","family":"Awad","sequence":"additional","affiliation":[{"name":"Medicinal and Aromatic Plants Research Institute, National Centre of Research,  Khartoum 11111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,2,11]]},"reference":[{"key":"ref_1","unstructured":"World Malaria Report 2013. Available online: http:\/\/www.who.int\/malaria\/publications\/world_malaria_report_2013\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum Malaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.gene.2005.09.010","article-title":"Acetylation and deacetylation of non-histone proteins","volume":"363","author":"Glozak","year":"2005","journal-title":"Gene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nrm2346","article-title":"The Rpd3\/Hda1 family of lysine deacetylases: From bacteria and yeast to mice and men","volume":"9","author":"Yang","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1119(01)00741-7","article-title":"The molecular biology of the SIR proteins","volume":"279","author":"Gasser","year":"2001","journal-title":"Gene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0166-6851(98)00177-7","article-title":"Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum","volume":"99","author":"Joshi","year":"1999","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cell.2005.01.037","article-title":"Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites","volume":"121","author":"Freitas","year":"2005","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nbt1272","article-title":"Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug","volume":"25","author":"Marks","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/icb.2011.97","article-title":"HDAC inhibitors in parasitic diseases","volume":"90","author":"Andrews","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1128\/AAC.00757-07","article-title":"Potent antimalarial activity of histone deacetylase inhibitor analogues","volume":"52","author":"Andrews","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3849","DOI":"10.1128\/AAC.00030-12","article-title":"Antimalarial activity of the anticancer histone deacetylase inhibitor SB939","volume":"56","author":"Sumanadasa","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2174\/156802609788085313","article-title":"Targeting histone deacetylase inhibitors for anti-malarial therapy","volume":"9","author":"Andrews","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1021\/jm801654y","article-title":"Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum","volume":"52","author":"Patel","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"36734","DOI":"10.1074\/jbc.M101287200","article-title":"Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen","volume":"276","author":"Phiel","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0920-9964(02)00357-2","article-title":"Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii","volume":"62","author":"Torrey","year":"2003","journal-title":"Schizophr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.exppara.2008.11.010","article-title":"Schistosoma mansoni: Developmental arrest of miracidia treated with histone deacetylase inhibitors","volume":"121","author":"Azzi","year":"2009","journal-title":"Exp. Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00280-014-2384-1","article-title":"Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers","volume":"73","author":"Wheler","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.1182\/blood-2013-12-546283","article-title":"Valproic acid in combination with all-trans retinoic acid and intensive induction therapy for acute myeloid leukemia in older patients","volume":"123","author":"Tassara","year":"2014","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00280-012-1986-8","article-title":"Phase I study of 5-aza-2'-deoxycytidine in combination with valproic acid in non-small-cell lung cancer","volume":"71","author":"Chu","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_20","unstructured":"FDA Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated October 7, 2011. NDA 018723\/S-037\/S-040\/S-043\/S-045\/S-046 Depakote (divalproex sodium) Tablets for Oral use FDA Approved Labeling Text dated 7 October 2011, Available online: http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/018723s037lbl.pdf."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2014). The UniProt consortium activities at the universal protein resource (UniProt). Nucleic Acids Res., 42, D191\u2013D198.","DOI":"10.1093\/nar\/gkt1140"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: A new generation of protein database search programs","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1016\/j.bmcl.2010.03.091","article-title":"Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides","volume":"20","author":"Bressi","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5254","DOI":"10.1016\/j.bmc.2008.03.005","article-title":"Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy","volume":"16","author":"Mukherjee","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/bioinformatics\/btm404","article-title":"Clustal W and Clustal X version 2.0","volume":"23","author":"Larkin","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1093\/protein\/12.2.85","article-title":"Twilight zone of protein sequence alignments","volume":"12","author":"Rost","year":"1999","journal-title":"Protein Eng."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/prot.10286","article-title":"Structure validation by C\u03b1 geometry: \u03d5, \u03c8 and C\u03b2 deviation","volume":"50","author":"Lovell","year":"2003","journal-title":"Proteins-Struct. Funct. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0076-6879(97)77022-8","article-title":"Verify3D: Assessment of protein models with three-dimensional profiles","volume":"277","author":"Eisenberg","year":"1997","journal-title":"Methods Enzymol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1003645","DOI":"10.1371\/journal.ppat.1003645","article-title":"Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni","volume":"9","author":"Marek","year":"2013","journal-title":"PLoS Pathog."},{"key":"ref_33","unstructured":"Labute, P., and Santavy, M. Locating Binding Sites in Protein Structures. Available online: http:\/\/www.chemcomp.com\/journal\/sitefind.htm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3519","DOI":"10.1073\/pnas.95.7.3519","article-title":"A role for histone deacetylase activity in HDAC1-mediated transcriptional repression","volume":"95","author":"Hassig","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1101\/gad.12.6.797","article-title":"Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo","volume":"12","author":"Kadosh","year":"1998","journal-title":"Genes Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.sbi.2011.08.004","article-title":"Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes","volume":"21","author":"Lombardi","year":"2011","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/prot.21082","article-title":"Protein-ligand docking: Current status and future challenges","volume":"65","author":"Sousa","year":"2006","journal-title":"Proteins"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1208\/s12248-012-9322-0","article-title":"Structure-based virtual screening for drug discovery: A problem-centric review","volume":"14","author":"Cheng","year":"2012","journal-title":"AAPS J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5243","DOI":"10.3390\/molecules19045243","article-title":"Integrated computational tools for identification of CCR5 antagonists as potential HIV-1 entry inhibitors: Homology modeling, virtual screening, molecular dynamics simulations and 3D QSAR analysis","volume":"19","author":"Moonsamy","year":"2014","journal-title":"Molecules"},{"key":"ref_40","unstructured":"Krieger, E. Yet Another Scientific Artificial Reality Application (YASARA). http:\/\/www.yasara.org\/."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/prot.22570","article-title":"Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8","volume":"77","author":"Krieger","year":"2009","journal-title":"Proteins"},{"key":"ref_42","unstructured":"Chemical Computing Group Inc Molecular Operating Environment (MOE). http:\/\/www.chemcomp.com\/."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1021\/jo070739s","article-title":"Zinc binding in HDAC inhibitors: A DFT study","volume":"72","author":"Wang","year":"2007","journal-title":"J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1016\/j.bmc.2005.04.001","article-title":"Theoretical study revealing the functioning of a novel combination of catalytic motifs in histone deacetylase","volume":"13","author":"Vanommeslaeghe","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6110","DOI":"10.1021\/ja111104p","article-title":"Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel","volume":"133","author":"Wu","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11636","DOI":"10.1021\/ja501548p","article-title":"Inhibition and mechanism of HDAC8 revisited","volume":"136","author":"Chen","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1002\/(SICI)1096-987X(199905)20:7<720::AID-JCC7>3.0.CO;2-X","article-title":"MMFF VI. MMFF94s option for energy minimization studies","volume":"20","author":"Halgren","year":"1999","journal-title":"J. Comput. Chem."},{"key":"ref_48","unstructured":"Edelsbrunner, H. (1995). Weighted Alpha Shapes, Department of Computer Science, University of Illinois."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1002\/jcc.20065","article-title":"Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations","volume":"25","author":"Mackerell","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F","article-title":"How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules?","volume":"21","author":"Wang","year":"2000","journal-title":"J. Comput. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/978-1-61779-465-0_25","article-title":"Assignment of protonation states in proteins and ligands: Combining pKa prediction with hydrogen bonding network optimization","volume":"819","author":"Krieger","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1021\/ci300264u","article-title":"Homology models of human all-trans retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced variant","volume":"52","author":"Elmabsout","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1021\/cb5003762","article-title":"Compromised structure and function of HDAC8 mutants identified in cornelia de lange syndrome spectrum disorders","volume":"9","author":"Decroos","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"26926","DOI":"10.1074\/jbc.M113.490706","article-title":"Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability","volume":"288","author":"Lauffer","year":"2013","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/3915\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:42:33Z","timestamp":1760215353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/3915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2,11]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,2]]}},"alternative-id":["ijms16023915"],"URL":"https:\/\/doi.org\/10.3390\/ijms16023915","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2,11]]}}}