Virtual Screening of Novel Hybrid Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Exploring Multiple Targeted Cancer Therapy by an In Silico Approach

Author(s): Ashish P. Shah*, Chhagan N. Patel

Journal Name: Current Cancer Therapy Reviews

Volume 16 , Issue 1 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. In silico methods are useful tool for the search and design of selective multi-target agents.

Objective: The objective of the present study was to design new hybrid compounds by linking the main structural unit of the NSAIDs with the benzothiazole and thiadiazole ring and to discover new hybrid NSAIDs as multi targeted anticancer agents through in silico approach.

Methods: Structure-based virtual screening was performed by applying ADMET filtration and Glide docking using Virtual screening Workflow. The docking studies were performed on three different types of receptors TNF-α, COX-II and protein kinase. Bioactivity prediction of screened compounds were done using Molinspiration online software tool.

Results: Out of the 54 designed compounds eighteen were screened on the basis of binding affinity on various receptors and ADMET filtration. Bioactivity prediction reveals that screened compounds may act through kinase inhibition or enzyme inhibition. Compounds 2sa, 5sa, 6sa and 7sa showed higher binding affinity with all three receptors.

Conclusion: The study concluded that compound 2sa, 5sa, 6sa, and 7sa could be further explored for multiple targeted cancer therapy.

Keywords: Virtual screening, docking, ADMET studies, novel hybrid NSAIDs, cancer, oncoproteins.

[1]
Massagué J, Batlle E, Gomis RR. Understanding the molecular mechanisms driving metastasis. Mol Oncol 2017; 11(1): 3-4.
[2]
Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 2018; 18(5): 309-24.
[3]
Han R, Hu M, Zhong Q, et al. Perfluorooctanesulphonate induces oxidative hepatic damage via mitochondria-dependent and NF-κB/TNF-α-mediated pathway. Chemosphere 2018; 191: 1056-64.
[4]
Jun JC, Rathore A, Younas H, Gilkes D, Polotsky VY. Hypoxia-inducible factors and cancer. Curr Sleep Med Rep 2017; 3(1): 1-10.
[5]
Jänne PA, Gray N, Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 2009; 8(9): 709-23.
[6]
Krishnamachary B, Stasinopoulos I, Kakkad S, et al. Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget 2017; 8(11): 17981-94.
[7]
Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell 2017; 168(1-2): 37-57.
[8]
Yadav MR, Barmade MA, Tamboli RS, Murumkar PR. Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer. Eur J Med Chem 2015; 105: 1-38.
[9]
Cristofanon S, Morceau F, Scovassi AI, Dicato M, Ghibelli L, Diederich M. Oxidative, multistep activation of the noncanonical NF-κB pathway via disulfide Bcl-3/p50 complex. FASEB J 2009; 23(1): 45-57.
[10]
Chen R, Alvero AB, Silasi DA, Mor G. Inflammation, Cancer and Chemoresistance: Taking Advantage of the Toll-Like Receptor Signaling Pathway. Am J Reprod Immunol 2007; 57(2): 93-107.
[11]
Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007; 117(5): 1175-83.
[12]
DasGupta S, Murumkar PR, Giridhar R, Yadav MR. Current perspective of TACE inhibitors: A review. Bioorg Med Chem 2009; 17(2): 444-59.
[13]
Vane JR, Warner TD. Nomenclature for COX-2 inhibitors. Lancet 2000; 356(9239): 1373-4.
[14]
Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12(12): 1063-73.
[15]
Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 2002; 190(3): 279-86.
[16]
Rayyan Y, Williams J, Rigas B. The role of NSAIDs in the prevention of colon cancer. Cancer Invest 2002; 20(7-8): 1002-11.
[17]
Sulciner ML, Gilligan MM, Zetter BR, Panigrahy D. Inflammation and Cancer: The Role of Lipid Signaling in the Continuum Between Two Ends of the Tumor Spectrum. In: Biomarkers of the Tumor Microenvironment. Cham: Springer; Germany 2017; pp. 167-93.
[18]
Wilhelm M, Schlegl J, Hahne H, et al. Mass-spectrometry-based draft of the human proteome. Nature 2014; 509(7502): 582-7.
[19]
Cohen P. Protein kinases - the major drug targets of the twenty-first century? Nat Rev Drug Discov 2002; 1(4): 309-15.
[20]
Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. Targeting cancer with kinase inhibitors. J Clin Invest 2015; 125(5): 1780-9.
[21]
Xie Y, Wang A, Lin J, et al. Mps1/TTK: A novel target and biomarker for cancer. J Drug Target 2017; 25(2): 112-8.
[22]
Liu X, Winey M. The MPS1 family of protein kinases. Annu Rev Biochem 2012; 81: 561-85.
[23]
Kumar V, Sharma S, Husain A. Synthesis and in vivo Anti-inflammatory and analgesic activities of oxadiazoles clubbed with benzothiazole nucleus. Int Curr Pharm J 2015; 4(12): 457-61.
[24]
Özdemir A, Sever B, Altıntop MD, et al. Synthesis and evaluation of new oxadiazole, thiadiazole, and triazole derivatives as potential anticancer agents targeting MMP-9. Molecules 2017; 22(7): 1109.
[25]
Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CA. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem 2007; 14(17): 1829-52.
[26]
Xie L, Huang J, Chen X, et al. Design, synthesis and biological evaluation of novel rapamycin benzothiazole hybrids as mTOR targeted anti-cancer agents. Chem Pharm Bull (Tokyo) 2016; 64(4): 346-55.
[27]
Kumar V, Krishna S, Siddiqi MI. Virtual screening strategies: Recent advances in the identification and design of anti-cancer agents. Methods 2015; 71: 64-70.
[28]
Levin JI, Chen JM, Laakso LM, et al. Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates. Bioorg Med Chem Lett 2005; 15(19): 4345-9.
[29]
Orlando BJ, Malkowski MG. Substrate-selective inhibition of cyclooxygeanse-2 by fenamic acid derivatives is dependent on peroxide tone. J Biol Chem 2016; 291(29): 15069-81.
[30]
Innocenti P, Woodward HL, Solanki S, et al. Rapid discovery of pyrido [3, 4-d] pyrimidine inhibitors of monopolar spindle kinase 1 (MPS1) using a structure-based hybridization approach. J Med Chem 2016; 59(8): 3671-88.


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 1
Year: 2020
Published on: 06 February, 2020
Page: [70 - 77]
Pages: 8
DOI: 10.2174/1573394715666190618114748

Article Metrics

PDF: 17
HTML: 2