• EIICHI AKAHO Faculty of Pharmaceutical Sciences, Kobe Gakuin Univercity, 1-1-3 Minatojima, Chuo-ku, Kobe, 6508586 Japan



Epigenetic drugs, Virtual screening, Auto Dock, Hydrogen bond, Histogram, Cluster, Histone H3B E6K mutant, DNA methyltransferase


Objective: Over the last 30 y cancer epigenetics research has grown extensively. It is note-worthy to recognize that epigenetic misregulation could substantiate the development of cancer and we need to continue to look for anti-neoplastic epi-drugs. Taking into consideration this phenomenon, our first aim is to search for an effective epi-drugs by virtual screening from ZINC database and to explore the validity of the virtual screening. The second aim is to explore a binding conformation of the top affinity ligands against macromolecules, by docking experiment.

Methods: The virtual screening was conducted by our Virtual Screening by Docking (VSDK) algorithm and procedure. Small molecules were randomly downloaded by ZINC database. For docking experiment, AutoDock 4.2.6 and AutoDock Tool were used.

Results: It took eight to ten hours for the successful virtual screening of the 2778 small compounds retrieved at random from ZINC database. Among histone H2B E76K mutant (HHEM) inhibitors and DNA methyltransferase (DNMT) inhibitors, the first ranked inhibitors were 1H-1,2,4-triazole-3,5-diamine and 2-ethyl-1,3,4-oxadiazole respectively.

Conclusion: As for the molecular structures obtained from virtual screening, most of the top ten HHEM and DNMT inhibitors contained 5-member rings. More than two times in affinity difference between the top and bottom ten compounds would indicate a successful virtual screening experiment. The histogram chart of AutoDock4 runs appeared in the lowest affinity region with two or three hydrogen bonds indicating a reliable conformation docking.


Download data is not yet available.


Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020:.GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 184 countries. CA Cancer J Clin 2021;71:209-49.

Siegel LS, Miller KD, Jmal M. Cancer statistics. CA Cancer J Clin 2020;70:7-30.

Forli S, Olson A. A forcefield with discrete displaceable waters and desolvation entropy hydrated ligand docking. J Med Chem 2012;55:623-38.

Bray F, Ferlay J, Soerjamataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 counties. CA: Cancer J Clin 2018;68:394-424.

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comp Chem 2010;31:466-61.

Singh R, Bassett E, Chakravarti1 A, Parthun M. Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function. Nucl Acid Res 2018;46:8665–78.

Mu TW, Ong DST, Wang YJ, Balch WE, Yates JR, Segatori L, Kelly JW. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 2008;134:769–81.

Cohen E, Paulsson JF, Blinder P, Burstyn Cohen T, Du D, Estepa G, et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 2009;139:1157–69.

Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC. Autophagy Induction as a therapeutic strategy for neurodegenerative diseases. J Mol Biol 2020;432:2799–821.

Yanjun M, Hendershot LM. The role of the unfolded protein response in tumor development: friend or foe. Nat Rev Cancer 2005;4:966-77.

Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discovery 2013;12:703-19.

Shi W, Chen Z, Li L, Liu H, Zhang R, Cheng Q, et al. Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells. J Cancer 2019;10:2035-46.

Longley DB, Johnson PG. Molecular mechanisms of drug resistance. J Phathol 2005;205:275-92.

Sang J, Kulkarni K, Watson GM, Ma X, Craik DJ, Henriques ST, et al. Evaluation of cyclic peptide inhibitors of the Grb7 breast cancer target: small change in cargo results in large change in cellular activity. Molecules 2019;24:1-19.

Peng SB, Zhang X, Paul D, Kays LM, Gough W, Stewart J, et al. Identification of LY251924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities a solid tumor and breast cancer metastatic models. Mol Cancer Ther 2014;14:480-90.

Khan MA, Tania M, Fu J. Epigenetic role of thymoquinone: impact on cellular mechanism and cancer therapeutics. Drug Discovery Today 2019;24:2315-22.

Shi YX, Sheng DQ, Cheng L, Song XY. Current landscape of epigenetics in lung cancer: focus on the mechanism and application. J Oncol 2019;2019:1-11.

Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell 2012;150:12-7.

Masui K, Harachi M, Webster K, Cavennee K, Mischel PS, Shibata N. Codependency of metabolism and epigenetics derives cancer progression: a review. Acta Histochem Cytochem 2020;53:1-10.

Clapiew CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of action and regulation of ATP-dependent chromatin-remodeling complexes. Nat Rev Mol Cell Bio 2017;18:207-422.

Fujisawa T, Filippakopoulos P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Bio 2017;18:246-62.

Trivedi A, Mehrotra A, Baum CE, Lewis B, Basuroy T, Blomquist T, et al. Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation. Epigen Chrom 2020;13:1-18.

Kozakov D, Clodfelter KH, Vakda S, Camacho CJ. Optimal clustering for detecting near-native conformations in protein docking. Biophys J 2005;89:867-75.

Niranos A, Cassaccia P. Bromodomains: translating the words of lysine acetylation into myelin injury and repair. Neurosci Lett 2017;625:4-10.

Strahl BD, Aills CD. The language of covalent histone modifications. Nature 2000;403:41-5.

Garcia Guede A, Vera O, Ibafiez-de-Caceres I. When oxidative stress meets epigenetics: implications in cancer development. Antioxidants 2020;9:1-26.

Shin DG, Bayarsaihan D. A novel epi-drug therapy based on the suppression of BET family epigenetic readers. Yale J Bio Med 2017;90:53-71.

Gupta R¸ Leon F, Rauth S, Batra SK, Ponnusamy MP. A systematic review on the implication of O-linked glycan branching and truncating enzymes on cancer progression and metastasis. Cells 2020;446:3-25.

Zarrer J, Haider MT, Smit DJ, Taipaleenmaki H. Pathological crosstalk between metastatic breast cancer cells and the bone microenvironment. Biomolecules 2020;10:1-20.

Hogan KA, Chini CS, Chini EN. The multi-faceted ectoenzyme CD38:.roles in immunomodulation, cancer, aging, and metabolic diseases. Front Immunol 2019;10:1-12.

Thomas C, Metrock K, Metrock K, Kodes U. Epigenic impacts upon prognosis and clinical management of choroid plexus tumors. J Neuro Oncol 2020;148:39-45.

Yuanjun L, Chan YT, Tan HY, Li S, Wang N, Feng Y. Epigenic regulation in human cancer: potential role of epi-drug in cancer therapy. Mol Cancer 2020;19:1-16.

Miranda Furtabo CL, Dos Santos Luciano MC, Silva Santos RD, Furtado GP, Moraes MO, Pessoa C. Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics 2019;14:1164-76.

Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE. A geometric approach to macromolecule ligand interactions. J Mol Biol 1982;161:269–88.

Pagadala NS, Khajamohiddin Syed, Tuszynski J. Software for molecular docking: a review. Biophys Rev 2017;9:91–102.

Morris GM, Goodsell DS, Pique ME, Lindstrom WL, Huey R, Forli S, et al. AutoDock, AutoGrid, AutoDock Tool. Scripps Research Institute. Cal, USA; 2004.

Awale M, Jin X, Rymond JL. Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints. J Chem Inf 2015;7:3.

Vidler LR, Fiippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, et al. Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. J Med Chem 2013;56:8673-88.

Ruiz Torres V, Encinar JA, Herranz Lopez M, Perez Sanchez A, Galiano V, Enrique Barrajon Catalan E, et al. An updated review on marine anticancer compounds: the use of virtual screening for the discovery of small-molecule cancer drugs. Molecules 2017;22:1-37.

Fischer A, Sellner M, Niranjan S, Smiesco M, Lill MA. Potential inhibitors novel coronavirus protease identified by virtual screening of 606 million compound. Int J Mol Sci 2020;21:3626-43.

N Baba, E Akaho. VSDK: virtual screening of small molecules using AutoDock vina on windows platform. Bioinformation 2011;6:387-8.

Protein Data Bank, RCSB PDB: Homepage; 2021.

ZINC. Available from: [Last accessed on 18 May 2021]

Facio. Available from: [Last accessed on 18 May 2021]

Zhang X, Huang H, Zhuang D, Nasser MI, Yang M, Zhu P. Biological clinical and epidemiological features of COVID-19, SARS and MERS and AutoDock simulation of ACE2. Infect Dis Poverty 2020;9:3-11.

French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Flecher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 2003;63:304-7.

Goodsell DS, Morris GM, Olson JA. Automated docking of flexible ligands; applications of AutoDock. J Mol Recognit 1996;9:1-5.

Ali HI, Tomita K, Akio E, Kawashima Y, Yamagishi T, Ikea H, et al. Antitumor studies-part II: structure-activity relationship study for flavin analogs including investigations on their in vitro antitumor assay and docking simulation into protein tyrosine kinase. Euro J Med Chem 2008;43:1376-89.

Ueda S, Tanaka S. AutoDock-GIST; Incorporating thermodynamics of active-site water into scoring function for accurate protein-ligand docking. Molecules 2016;21:1064-24.

Zarrer J, Haider MT, Smit DJ, Taipaleenmaki H. Pathological crosstalk between metastatic breast cancer cells and the bone microenvironment. Biomolecules 2020;10:1-20.

Morris GM, Lim Wilby M. Molecular docking. Methods in molecular biology. Humana Press: Totowa, NJ, USA; 2008. p. 365-82.

Kozamov D, Codfelter KH, Vajda S, Camacho CJ. Optimal clustering for detecting near-native conformations. Biophys J 2005;89:867–85.

Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Gen Bio 2019;20:1-16.

Arimura Y, Ikura M, Fujita R, Noda N, Kobayashi W, Horikoshi N, et al. Cancer-associated mutations of histones H2B, H3.1 and H2A. Z1 affect the structure and stability of the nucleosome. Nucl Acid Res 2018;46:10007-18.

Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-COV-2 by full-length human ACE2. Science 2020;367:1444-8.

Riza H, Fahrurruji A, Wicaksono A, Nugroho AK, Martono S. Docking study of methyl hesperidin as nucleoside transcriptase inhibitor. Int J Pharm Pharm Sci 2018;10:85-9.

Chellam J, Deepai R. Computational biological study of aromatase inhibitors docking with human placental aromatase cytochrome p450. Int J Pharm Pharm Sci 2016;7:93-7.

Govindarasu M, Palani M, Vaiyapuri MI. In silico docking studies on kaempferitrin with diverse inflammatory and apoptotic proteins functional approach towards the colon cancer. Int J Pharm Pharm Sci 2017;9:199-204.

Tanisa AN, Riadhi R, Yanuar A. Virtual screening of beta-secretase 1 (BACE 1) inhibitors in the Indonesian herbal database as using AutoDock and AutoDock Vina. Asian J Pharm Clin Res 2017;10:148-52.

Chahdrasekaran R, Sivaraman T, Sivaramakrishnan S, Kumar JJ. A computational approach on understanding structural interactions of envelope protein of dengue virus bound with squalene, a prototype anti-viral compound. Int J Pharm Pharm Sci 2019;11:1113-6.

Sharma A, Kunwar S, Agarwal V, Singh C, Sharma MD, Chauhan N. Molecular docking: an explanatory approach in structure-based drug designing discovery. Int J Pharm Pharm Sci 2021;13:6-12.

Ibrahin H, Elsharawy FS, Elhassab M, Shabana S, Haggag G. Phytochemical screening and biological evaluation of Dypsis Leptocheilog leaves extract and molecular docking study of the isolated compounds. Int J Pharm Pharm Sci 2020;12:106-13.

Musfiroh I, Khatami HA, Megantara S, Muchtaridi M. Molecular dynamic simuation of asiatic acid derivatives complex with inducible nitric oxide synthase enzyme as an anti-inflammatory. Int J Appl Pharm 2021;13:32-8.

Pradeelp S, Shrungesh KT, Prashantha N, Majadevan KM. Synthesis in vitro antibacterial, toxicology and macromolecular docking anticancer activity of novel N-[(2-chloroquinolin-3-yl) methylidene]-2-anilin schiff bases. Int J Curr Pharm Res 2015;7:37-46.



How to Cite




Original Article(s)