Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Searching for Potential HDAC2 Inhibitors: Structure-activity Relationship Studies on Indole-based Hydroxamic Acids as an Anticancer Agent

Author(s): Ekta Shirbhate, Divya, Preeti Patel, Vijay K. Patel, Ravichandran Veerasamy, Prabodh C. Sharma and Harish Rajak*

Volume 17, Issue 7, 2020

Page: [905 - 917] Pages: 13

DOI: 10.2174/1570180817666200103125701

Price: $65

Abstract

Aim: To predict the most potent indole based HDAC2 inhibitors from several scientific reports through the process of lead identification and SAR development.

Background: The current scenario is observing Histone Deacetylase (HDAC) as an alluring molecular target for the designing and development of drugs for cancer treatment.

Objective: To identify the lead and establish structure-activity correlation among indole based hydroxamic acid to find out promising HDAC2 based anticancer agent.

Methods: A dataset containing 59 molecules was analyzed using structure and ligand-based integrated approach comprising atom-based 3D-QSAR (Quantitative Structure-Activity Relationship) and pharmacophore study, e-pharmacophore mapping and molecular modeling methodologies. The finest model was prepared by amalgamating the properties of electronegativity, polarizability, Vander Waals forces and other conformational aspects.

Results: The result of 3D QSAR analysis, performed for 4 PLS factor, provided the following statistical information: R2 = 0.9461, Q2 = 0.7342 and low standard of deviation SD = 0.1744 for hypothesis ADDDH.10 and R2 = 0.9444, Q2= 0.7858 and again low standard of deviation SD = 0.1795 for hypothesis DDHRR.12. The XP molecular docking showed intermolecular interactions of small molecules with amino acids such as GLY154, HIP145, PHE210, HIE183, internal H2O and Zn2+.

Conclusion: The interpretation of data generated as a result of this investigation clearly hints about the better biological activity of test compounds as compared to SAHA. Hence, the outcome of these structure and ligand-based integrated studies could be employed for the design of novel arylindole derivatives as a potent HDAC inhibitor.

Keywords: Hydroxamate, HDAC inhibitors, pharmacophore, 3D QSAR, docking studies, anticancer agents.

« Previous Next »
Graphical Abstract

[1]
Kinzler, K.W.; Vogelstein, B. Cancer-susceptibility genes. Nature, 1997, 386(6627), 761-763.
[2]
Patel, P.; Patel, V.K.; Singh, A.; Jawaid, T.; Mehnaz, K.; Rajak, H. Identification of hydroxamic acid based selective HDAC1 inhibitors: Computer aided drug design studies. Curr Comp. Aid. Drug Des., 2018, 14, 1-22.
[3]
Suzuki, T.; Miyata, N. Non-hydroxamate histone deacetylase inhibitors. Curr. Med. Chem., 2005, 12(24), 2867-2880.
[http://dx.doi.org/10.2174/092986705774454706] [PMID: 16305476]
[4]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[5]
Patel, P.; Singh, A.; Patel, V.K.; Jain, D.K.; Veerasamy, R.; Rajak, H. Pharmacophore based 3D-QSAR, virtual screening and docking studies on novel series of HDAC inhibitors with thiophene linkers as anticancer agents. Comb. Chem. High Throughput Screen., 2016, 19(9), 735-751.
[http://dx.doi.org/10.2174/1386207319666160801154415] [PMID: 27487787]
[6]
Rajak, H.; Singh, A.; Raghuwanshi, K.; Kumar, R.; Dewangan, P.K.; Veerasamy, R.; Sharma, P.C.; Dixit, A.; Mishra, P. A structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity. Curr. Med. Chem., 2014, 21(23), 2642-2664.
[http://dx.doi.org/10.2174/09298673113209990191] [PMID: 23895688]
[7]
Dung, T.M.; Dung, P.T.P.; Oanh, D.T.K.; Hai, P.T.; Huong, T.T.; Loi, V.D.; Hahn, H.; Han, B.W.; Kim, J.; Han, S.B.; Nam, N.H. Novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides as histone deacetylase inhibitors and antitumor agents. Med. Chem., 2015, 11(8), 725-735.
[http://dx.doi.org/10.2174/1573406411666150702130633] [PMID: 26133355]
[8]
Nam, N.H.; Parang, K. Current targets for anticancer drug discovery. Curr. Drug Targets, 2003, 4(2), 159-179.
[http://dx.doi.org/10.2174/1389450033346966] [PMID: 12558068]
[9]
Dung, D.T.M.; Hai, P.T.; Duong, T.A.; Huong, L.T.T.; Yen, N.T.K.; Han, B.W.; Park, E.J.; Choi, Y.J.; Kang, J.S.; Hue, V.T.M.; Han, S.B.; Nam, N.H. Novel hydroxamic acids incorporating 1-((1H-1,2,3-Triazol-4-yl) methyl)-3-hydroxyimino-indolin-2-ones: synthesis, biological evaluation and SAR analysis. J. Chem. Sci., 2018, 130(63), 1-13.
[http://dx.doi.org/10.1007/s12039-018-1472-x]
[10]
Witt, O.; Deubzer, H.E.; Milde, T.; Oehme, I. HDAC family: What are the cancer relevant targets? Cancer Lett., 2009, 277(1), 8-21.
[http://dx.doi.org/10.1016/j.canlet.2008.08.016] [PMID: 18824292]
[11]
de Ruijter, A.J.; van Gennip, A.H.; Caron, H.N.; Kemp, S.; van Kuilenburg, A.B. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J., 2003, 370(Pt 3), 737-749.
[http://dx.doi.org/10.1042/bj20021321] [PMID: 12429021]
[12]
Gray, S.G.; Ekström, T.J. The human histone deacetylase family. Exp. Cell Res., 2001, 262(2), 75-83.
[http://dx.doi.org/10.1006/excr.2000.5080] [PMID: 11139331]
[13]
Minucci, S.; Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer, 2006, 6(1), 38-51.
[http://dx.doi.org/10.1038/nrc1779] [PMID: 16397526]
[14]
Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5(9), 769-784.
[http://dx.doi.org/10.1038/nrd2133] [PMID: 16955068]
[15]
Dokmanovic, M.; Marks, P.A. New clinical developments in histone deacetylase inhibitors for epigenetic therapy for cancer. Expert Opin. Investig. Drugs, 2005, 14, 1497-1511.
[16]
Huong, T.T.L.; Cuong, L.V.; Huong, P.T.; Thao, T.P.; Huong, L.T.T.; Dung, P.T.P.; Oanh, D.T.K.; Juong, N.T.M.; Quan, H.V.; Vu, T.K.; Kim, J.; Lee, J.H.; Han, S.B.; Hai, P.T.; Nam, N.H. Exploration of some indole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Chem. Pap., 2017, 71, 1759-1769.
[http://dx.doi.org/10.1007/s11696-017-0172-1]
[17]
Glaser, K.B. HDAC inhibitors: clinical update and mechanism-based potential. Biochem. Pharmacol., 2007, 74(5), 659-671.
[http://dx.doi.org/10.1016/j.bcp.2007.04.007] [PMID: 17498667]
[18]
West, A.C.; Johnstone, R.W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest., 2014, 124(1), 30-39.
[http://dx.doi.org/10.1172/JCI69738] [PMID: 24382387]
[19]
Huong, T.T.L.; Dung, D.T.M.; Huan, N.V.; Cuong, L.V.; Hai, P.T.; Huong, L.T.T.; Kim, J.; Kim, Y.G.; Han, S.B.; Nam, N.H. Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity. Bioorg. Chem., 2017, 71, 160-169.
[http://dx.doi.org/10.1016/j.bioorg.2017.02.002] [PMID: 28196602]
[20]
Dallavalle, S.; Cincinelli, R.; Nannei, R.; Merlini, L.; Morini, G.; Penco, S.; Pisano, C.; Vesci, L.; Barbarino, M.; Zuco, V.; De Cesare, M.; Zunino, F. Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Eur. J. Med. Chem., 2009, 44(5), 1900-1912.
[http://dx.doi.org/10.1016/j.ejmech.2008.11.005] [PMID: 19084294]
[21]
Schäfer, S.; Jung, M. Chromatin modifications as targets for new anticancer drugs. Arch. Pharm. (Weinheim), 2005, 338(8), 347-357.
[http://dx.doi.org/10.1002/ardp.200500984] [PMID: 16041839]
[22]
Biel, M.; Wascholowski, V.; Giannis, A. Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes. Angew. Chem. Int. Ed. Engl., 2005, 44(21), 3186-3216.
[http://dx.doi.org/10.1002/anie.200461346] [PMID: 15898057]
[23]
Miller, T.A.; Witter, D.J.; Belvedere, S. Histone deacetylase inhibitors. J. Med. Chem., 2003, 46(24), 5097-5116.
[http://dx.doi.org/10.1021/jm0303094] [PMID: 14613312]
[24]
Singh, S.K.; Patra, A. Evaluation of adaptogenic potential of Polygonatum cirrhifolium (Wall.) Royle: In vitro, in vivo and in silico studies. S. Afr. J. Bot., 2019, 121, 159-177.
[http://dx.doi.org/10.1016/j.sajb.2018.10.022]
[25]
Jorgensen, W.L.; Maxwell, D.S.; Tirado-Rives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc., 1996, 118(45), 11225-11236.
[http://dx.doi.org/10.1021/ja9621760]
[26]
Patel, V.K.; Chouhan, K.S.; Singh, A.; Jain, D.K.; Veerasamy, R.; Singour, P.K.; Pawar, R.S.; Rajak, H. Development of structure activity correlation model on Azetidine-2-ones as tubulin polymerization inhibitors. Lett. Drug Des. Discov., 2015, 12, 351-365.
[http://dx.doi.org/10.2174/1570180811666141010000110]
[27]
Salam, N.K.; Nuti, R.; Sherman, W. Novel method for generating structure-based pharmacophores using energetic analysis. J. Chem. Inf. Model., 2009, 49(10), 2356-2368.
[http://dx.doi.org/10.1021/ci900212v] [PMID: 19761201]
[28]
Watts, K.S.; Dalal, P.; Murphy, R.B.; Sherman, W.; Friesner, R.A.; Shelley, J.C. ConfGen: a conformational search method for efficient generation of bioactive conformers. J. Chem. Inf. Model., 2010, 50(4), 534-546.
[http://dx.doi.org/10.1021/ci100015j] [PMID: 20373803]
[29]
Dixon, S.L.; Smondyrev, A.M.; Knoll, E.H.; Rao, S.N.; Shaw, D.E.; Friesner, R.A. PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J. Comput. Aided Mol. Des., 2006, 20(10-11), 647-671.
[http://dx.doi.org/10.1007/s10822-006-9087-6] [PMID: 17124629]
[30]
Golbraikh, A.; Tropsha, A. Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection. J. Comput. Aided Mol. Des., 2002, 16(5-6), 357-369.
[http://dx.doi.org/10.1023/A:1020869118689] [PMID: 12489684]

Rights & Permissions Print Cite
Article Metrics
20
© 2024 Bentham Science Publishers | Privacy Policy