STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES
DOI:
https://doi.org/10.22159/ijpps.2018v10i3.22735Keywords:
3D-QSAR, e-pharmacophore mapping, Ligand and structure-based designing, Docking, Pyrazole analogsAbstract
Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.
Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.
Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.
Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.
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Drwal MN, Griffith R. Combination of ligand-and structure-based methods in virtual screening. Drug Disc Today Tech 2013;10:395-401.
Olivier S, Maria AM, Bruno OV. Combining ligand-and structure-based methods in drug design projects. Curr Comput Aided Drug Des 2008;4:250-8.
El-Zayat AA, Degen D, Drabek S, Clark GM, Pettit GR, Von Hoff DD. In vitro evaluation of the antineoplastic activity of combretastatin A-4, a natural product from combretum caffrum (arid shrub). Anticancer Drugs 1993;4:19-25.
Yuanita E, Pranowo HD, Jumina J, Mustofa M. Design of hydroxy xanthones derivatives as anticancer using quantitative structure-activity relationship. Asian J Pharm Clin Res 2016;9:180-5.
Juliet AM, Cn H, Aanandhi MV. Computational studies of purine derivative using multiforms of human polypeptides 1 as a target enzyme for anticancer agents. Asian J Pharm Clin Res 2017;10:292-6.
Pradeep PS, Shrungesh Kumar TO, Prashantha N, Mahadevan KM. Synthesis, in vitro antibacterial, toxicity and molecular docking anticancer activity of novel N-[(2-chloroquinolin-3-yl) methylidene]-2-aniline schiff's bases. Int J Curr Pharm Res 2015;7:37-46.
Manal M, Chandrasekar MJ, Gomathi Priya J, Nanjan MJ. Inhibitors of histone deacetylase as antitumor agents: a critical review. Bioorg Chem 2016;67:18-42.
Rajak H, Singh A, Raghuwanshi K, Kumar R, Dewangan PK, Veerasamy R, et al. A structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity. Curr Med Chem 2014;21:2642-64.
Chen JB, Chern TR, Wei TT, Chen CC, Lin JH, Fang JM. Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase for cancer treatment. J Med Chem 2013;56:3645-55.
Guerrant W, Patil V, Canzoneri JC, Oyelere AK. Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. J Med Chem 2012;55:1465-77.
Mwakwari SC, Guerrant W, Patil V, Khan SI, Tekwani BL, Gurard-Levin ZA, et al. Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton. J Med Chem 2010;53:6100-11.
Canzoneri JC, Chen PC, Oyelere AK. Design and synthesis of novel histone deacetylase inhibitor derived from nuclear localization signal peptide. Bioorg Med Chem Lett 2009;19:6588-90.
Ding C, Chen S, Zhang C, Hu G, Zhang W, Li L, et al. Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinoline derivatives possessing hydroxamic acid moiety for cancer therapy. Bioorg Med Chem 2017;25:27-37.
Guerrant W, Patil V, Canzoneri JC, Yao LP, Hood R, Oyelere AK. Dual-acting histone deacetylase-topoisomerase I inhibitors. Bioorg Med Chem Lett 2013;23:3283-7.
Sun Q, Yao Y, Liu C, Li H, Yao H, Xue X, et al. Design, synthesis, and biological evaluation of novel histone deacetylase 1 inhibitors through click chemistry. Bioorg Med Chem Lett 2013;23:3295-9.
Yao Y, Liao C, Li Z, Wang Z, Sun Q, Liu C, et al. Design, synthesis, and biological evaluation of 1, 3-disubstituted-pyrazole derivatives as new class I and IIb histone deacetylase inhibitors. Eur J Med Chem 2014;86:639-52.
Ligprep, version 2.5, Schrödinger, LLC, New York, NY; 2012.
Phase, version 3.4, Schrödinger, LLC, New York, NY; 2012.
Watts KS, Dalal P, Murphy RB, Sherman WR, Friesner A, Shelley JC. Conf gen: a conformational search method for efficient generation of bioactive conformers. J Chem Inf Model 2010;50:534-46.
Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA. 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;19:647-67.
Golbraikh A, Tropsha A. Predictive QSAR modelling based on diversity sampling of experimental datasets for the training and test set selection. J Comput Aided Mol Des 2002;16:357-69.
Glide, version 5.8, Schrödinger, LLC, New York, NY; 2012.
Protein preparation wizard Schrödinger, LLC, New York, NY; 2012.
Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on the conformational energetics of organic liquids. J Am Chem Soc 1996;118:11225-36.
Li X, Li Y, Cheng T, Liu Z, Wang R. Evaluation of the performance of four molecular docking programs on a diverse set of protein-ligand complexes. J Comput Chem 2010;31:2109-25.
Cross JB, Thompson DC, Rai BK, Baber JC, Fan KY, Hu Y, et al. Comparison of several molecular docking programs: pose prediction and virtual screening accuracy. J Chem Inf Model 2009;49:1455-74.
Zhou Z, Felts AK, Friesner RA, Levy RM. Comparative performance of several flexible docking programs and scoring functions: enrichment studies for a diverse set of pharmaceutically relevant targets. J Chem Inf Model 2007;47:1599-608.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.
Salam NK, Nuti R, Sherman W. Novel method for generating structure-based pharmacophores using energetic analysis. J Chem Inf Model 2009;49:2356-68.
Lokwani D, Shah R, Mokale S, Shastry P, Shinde D. Development of energetic pharmacophore for the designing of 1,2,3,4-tetrahydropyrimidine derivatives as selective cyclooxygenase-2 inhibitors. J Comput Aided Mol Des 2012;26:267-77.
Singh KD, Kirubakaran P, Nagarajan S, Sakkiah S, Muthusamy K, Velmurgan D, et al. Homology modelling, molecular dynamics, e-pharmacophore mapping and docking study of chikungunya virus nsP2 protease. J Mol Model 2012;18:39-51.
Loving K, Salam NK, Woody S. Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation. J Comput Aid Mol Des 2009;23:541-54.
Wu R, Lu Z, Cao Z, Zhang Y. Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel. J Am Chem Soc 2011;133:6110-3.
Chen Y, Li H, Tang W, Zhu C, Jiang Y, Zou J, et al. 3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment. Eur J Med Chem 2009;44:2868-76.
Ononye SN, Van Heyst MD, Oblak EZ, Zhou W, Ammar M, Anderson AC, et al. Tropolones as lead-like natural products: the development of potent and selective histone deacetylase inhibitors. ACS Med Chem Lett 2013;4:757-61.
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