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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Quantitative Structure-Activity Relationship (QSAR) Modelling of Indomethacin Derivatives Using Regression Analysis

In Press, (this is not the final "Version of Record"). Available online 10 October, 2023
Author(s): Neerja Shukla and Bechan Sharma*
Published on: 10 October, 2023

DOI: 10.2174/0109298673245890231004152136

Price: $95

Abstract

Background: Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) used for medication to reduce fever, spondylitis, or shoulder pain. It mainly works by the inhibition of prostaglandins, the endogenous signaling molecules.

Methods: Fifteen indomethacin derivatives have been analyzed in relation to their physicochemical and molecular properties. Two-dimensional (2D) structures of fifteen indomethacin derivatives were drawn using the ACD Lab Chem Sketch version. Most of the topological parameters, such as wiener index (W), mean wiener index (Wa), Balaban indices (J), Balaban centric index (BAC), and molecular connectivity (χ), were calculated by using E Dragon software. The most common molecular file formats accepted in E-Dragon software were SMILES notations created online by Babel software and 2D structures of various derivatives, which were converted into 3D optimized structures using online CORINA, provided by Molecular Networks GMBH. 3D structures of compounds were also drawn on Gauss View software for calculations of various density functional theory (DFT) based quantum chemical descriptors, such as total energy (TE), softness (S), hardness (η), chemical potential (μ), highest occupied molecular orbital energy (HOMO), and lowest unoccupied molecular orbital energy (LUMO). All species were fully optimized in the gas phase with a 6-31+G* basis set. The harmonic vibrational frequency calculations were used to confirm that the optimized structures were minima, as characterized by positive vibrational frequencies.

Results: Combinations of various descriptors, such as D, ID, IOR, Log P, Mr, Mv, Mw, Pc, BAC, Pz, St, W, Wa, 0χ, 1χ, 2χ,3χ,4χ, 5χ, and Xeq have been found to be significant for modeling of activity. QSAR model no. 2: pIC50= -20.605 (±6.600) IOR - 0.747 (±0.454) I1 -5.083 (±3.478) Xeq + 51.647 optimized with empirical parameters with high statistical quality (R= 0.921, R2=0.848) was found to be the best model obtained.

Conclusion: The QSAR model obtained suggests that substituents with a lesser value of the index of refraction and less electronegative groups were favourable for the activity, whereas indomethacin derivatives with a CH2CH2NHCONH (CH2)3ONO2 group at R1 position were unfavourable for the activity. The results were critically discussed based on regression data and cross-validation techniques. Pogliani factor Q and the results of the LOO (leave-one-out) method confirmed the reliability and predictability of the proposed models that could be highly beneficial for the future designing of new analogues with higher potency.

[1]
Ramos-Inza, S.; Encío, I.; Raza, A.; Sharma, A.K.; Sanmartín, C.; Plano, D. Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: Identification of a Se-indomethacin analog as a potential therapeutic for breast cancer. Eur. J. Med. Chem., 2022, 244, 114839.
[http://dx.doi.org/10.1016/j.ejmech.2022.114839]
[2]
Bardia, A.; Olson, J.E.; Vachon, C.M.; Lazovich, D.; Vierkant, R.A.; Wang, A.H.; Limburg, P.J.; Anderson, K.E.; Cerhan, J.R. Effect of aspirin and other NSAIDs on postmenopausal breast cancer incidence by hormone receptor status: results from a prospective cohort study. Breast Cancer Res. Treat., 2011, 126(1), 149-155.
[http://dx.doi.org/10.1007/s10549-010-1074-x] [PMID: 20669045]
[3]
Perontsis, S.; Geromichalou, E.; Perdih, F.; Hatzidimitriou, A.G.; Geromichalos, G.D.; Turel, I.; Psomas, G. Synthesis, structural determination, in vitro and in silico biological evaluation of divalent or trivalent cobalt complexes with indomethacin. J. Inorg. Biochem., 2020, 212, 111213.
[http://dx.doi.org/10.1016/j.jinorgbio.2020.111213] [PMID: 32889129]
[4]
Wang, H.; Chang, Z.; Cai, G.; Yang, P.; Chen, J.; Yang, S.; Guo, Y.; Wang, M.; Zheng, X.; Lei, J.; Liu, P.; Zhao, D.; Wang, J. The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants. Acta Pharmacol. Sin., 2022, 43(4), 1024-1032.
[http://dx.doi.org/10.1038/s41401-021-00738-w] [PMID: 34321613]
[5]
Jain, H.K. QSAR analysis of Indomethacin derivatives as selective COX-2 inhibitors. Internet Electron. J. Mol. Des., 2006, 5(4), 224-236.
[6]
Obata, T.; Shiratani, S.; Nada, T.; Kasaya, Y.; Arisawa, M.; Shuto, S.; Tanaka, M. Structure-activity relationship of indomethacin derivatives as IDO1 inhibitors. Anticancer Res., 2021, 41(5), 2287-2296.
[http://dx.doi.org/10.21873/anticanres.15004] [PMID: 33952454]
[7]
Sava, A.; Buron, F.; Routier, S.; Panainte, A.; Bibire, N.; Constantin, S.M.; Lupașcu, F.G.; Focșa, A.V.; Profire, L. Design, synthesis, in silico and in vitro studies for new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold. Int. J. Mol. Sci., 2021, 22(13), 7079.
[http://dx.doi.org/10.3390/ijms22137079] [PMID: 34209248]
[8]
Nabil, M.; El Raey, M.A.; Abdo, W.; Abdelfattah, M.A.O.; El-Shazly, A.M.; Sobeh, M.; Mahmoud, M.F. Gastro-protective effects of Albizia anthelmintica leaf extract on Indomethacin-induced gastric ulcer in wistar rats: in silico and in vivo studies. Antioxidants, 2021, 10(2), 176.
[http://dx.doi.org/10.3390/antiox10020176] [PMID: 33530540]
[9]
Srivastava, A.K.; Shukla, N.; Pathak, V.K. Quantitative Structure Activity Relationship (QSAR) Studies on a series of off-target ion channel selective diltiazem sodium derivatives. J. Indian Chem. Soc., 2010, 87, 1-7.
[10]
John, A. Drugs for Treating Orofacial Pain Syndromes. Pharmacol. Therap. Dent., 2015, 384-385.
[11]
Srivastava, A.K.; Shukla, N.; Pandey, A.; Srivastava, A. QSAR based modeling on a series of α-hydroxy amides as a novel class of bradykinin B1 selective antagonists. J. Saudi Chem. Soc., 2011, 15(3), 215-220.
[http://dx.doi.org/10.1016/j.jscs.2010.09.001]
[12]
Srivastava, A.K.; Pandey, A.; Srivastava, A.; Shukla, N. QSAR based modeling of hepatitis C virus NS5B inhibitors. J. Saudi Chem. Soc., 2011, 15(1), 25-28.
[http://dx.doi.org/10.1016/j.jscs.2010.09.007]
[13]
Srivastava, A.K.; Shukla, N. Quantitative structure activity relationship (QSAR) studies on a series of imidazole derivatives as novel ORL1 receptor antagonists. J. Saudi Chem. Soc., 2013, 17(3), 321-328.
[http://dx.doi.org/10.1016/j.jscs.2011.04.014]
[14]
Sharma, D.; Shukla, S.D. Neuroprotection: It’s phytoremediation (theoretical perspective). IJGHC, 2013, 2, 1118-1131.
[15]
Shukla, N.; Srivastava, A.K. QSAR based modeling on a novel series of 2-chlorobenzamide derivatives as potent P2X (7) receptor antagonist. Oxid. Commun., 2014, 37(1), 290-300.
[16]
Srivastava, A.K.; Shukla, N.; Pathak, V.K. Quantitative Structure Activity Relationship (QSAR) studies on a series of carbamate appended N-alkylsulfonamides as inhibitors of peptide amyloid-β (Aβ). Oxid. Commun., 2013, 36(4), 1090-1101.
[17]
Shukla, N.; Srivastava, A.K. QSAR studies on a novel cyclohexanamine class of human serotonin transporter (hSERT) inhibitory activity. Oxid. Commun., 2013, 36(1), 133-142.
[18]
Srivastava, A.K.; Shukla, N. QSAR-based modelling on a novel series of pyrimidine-4-carboxamides as antagonists of the human a1 receptor. Oxid. Commun., 35(2), 423-437.
[19]
Diudea, M.V. QSPR/QSAR StudiesforMolecularDescriptors.NovaScience; Huntington: NewYork, 2000.
[20]
QSAR methods & applications; Gyandhara International Academy Publications: Thane, Mumbai, 2013.
[21]
Sahu, R.; Yadav, P.K.; Mishra, P.; Shukla, N. Identification, and characterization of a novel therapeutic drugtarget in Mycobacterium abscessus by in silico method. IJGHC, 2019, 8, 091-107.

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