Login Register Cart 0
Central Nervous System Agents in Medicinal Chemistry

Central Nervous System Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

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

Identification of Pharmacophore Responsible for the JNK3 Enzyme Inhibition using KPLS-based QSAR Analysis

Author(s): Ravi Kumar Rajan*, Maida Engels and Umaa Kuppuswamy

Volume 26, Issue 1, 2026

Published on: 03 March, 2025

Page: [63 - 78] Pages: 16

DOI: 10.2174/0118715249345667250216034023

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Background: The pharmacophoric approach relies on the theory of possessing ubiquitous chemical functionalities, and carrying a uniform spatial conformation that provides a route to enhanced potency on the same target receptor. JNK3, also known as c-Jun N-terminal kinase 3, is a protein kinase that plays a crucial role in various cellular processes, particularly in the central nervous system (CNS). In this study, a kernel-based partial least square (KPLS)- based Two-dimensional Quantitative structural activity relationship (2D QSAR) model to predict pharmacophores responsible for c-Jun-N-terminal kinase 3 (JNK3) inhibition.

Methods: A library of small molecule JNK3 inhibitors was created from the literature, and a predictive model was built using Canvas 2.6.

Results: The analysis revealed key structural determinants of activity. Compounds with high pIC50 values (>6) showed numerous favorable contributions, particularly secondary benzamide nitrogen and methylene groups. Steric effects were more influential than inductive effects, with bulkier groups like t-butyl reducing activity. Positive contributions were observed with OH, OCH3, and -F substituents, while unfavorable effects were linked to tertiary nitrogen, methyl, and primary amino groups. Substituted sulphonamides and benzotriazole moieties enhanced activity unless modified with amino or carbonyl groups. Favorable contributions were noted for terminal heterocyclic rings like pyrimidinyl acetonitrile, whereas phenyl substitutions and certain piperazine configurations were detrimental. Hydrogen in the urea moiety and avoiding bulky substitutions were crucial for activity. These insights guide the design of potent JNK3 inhibitors.

Conclusion: The present study highlights the significant impact of substituents on molecular activity, with steric effects, particularly on the phenyl ring, playing a dominant role. Favorable contributions are linked to substitutions like hydroxyl, methoxy, and fluorine, while bulky and meta substitutions reduce activity. Functional groups like unsubstituted sulfonamide or free hydrogen in urea are crucial for activity. Insights into steric, electronic, and positional factors, combined with analysis of JNK3 inhibitors, will guide the design of more selective molecules.

Keywords: KPLS, QSAR, JNK3, pharmacophore, canvas 2.6, IC50.

Erratum In:
Identification of Pharmacophore Responsible for the JNK3 Enzyme Inhibition using KPLS-based QSAR Analysis

« Previous Next »

Graphical Abstract

Graphical abstract illustrating key findings of the study

[1]
Pk, N.; Rajan, R.K.; Nanchappan, V.; Karuppaiah, A.; Chandrasekaran, J.; Jayaraman, S.; Gunasekaran, V. C-Glucosyl Xanthone derivative Mangiferin downregulates the JNK3 mediated caspase activation in Almal induced neurotoxicity in differentiated SHSY-5Y neuroblastoma cells. Toxicol. Mech. Methods, 2023, 33(9), 707-718.
[http://dx.doi.org/10.1080/15376516.2023.2237106] [PMID: 37455591]
[2]
Rajan, R.K.; Kumar, R.P.; Ramanathan, M. Piceatannol improved cerebral blood flow and attenuated JNK3 and mitochondrial apoptotic pathway in a global ischemic model to produce neuroprotection. Naunyn Schmiedebergs Arch. Pharmacol., 2024, 397(1), 479-496.
[http://dx.doi.org/10.1007/s00210-023-02616-0] [PMID: 37470802]
[3]
Rajan, R.K.; Ramanathan, M. Piceatannol selectively inhibited the JNK3 enzyme and augmented apoptosis through inhibition of Bcl‐2/Cyt‐c/caspase‐dependent pathways in the oxygen-glucose deprived SHSY‐5Y cell lines: In silico and in vitro study. Chem. Biol. Drug Des., 2024, 103(2), e14458.
[http://dx.doi.org/10.1111/cbdd.14458] [PMID: 38383061]
[4]
Musi, C.A.; Agrò, G.; Santarella, F.; Iervasi, E.; Borsello, T. JNK3 as therapeutic target and biomarker in neurodegenerative and neurodevelopmental brain diseases. Cells, 2020, 9(10), 2190.
[http://dx.doi.org/10.3390/cells9102190] [PMID: 32998477]
[5]
Busquets, O.; Espinosa-Jiménez, T.; Ettcheto, M.; Olloquequi, J.; Bulló, M.; Carro, E.; Cantero, J.L.; Casadesús, G.; Folch, J.; Verdaguer, E.; Auladell, C.; Camins, A. JNK1 and JNK3: Divergent functions in hippocampal metabolic-cognitive function. Mol. Med., 2022, 28(1), 48.
[http://dx.doi.org/10.1186/s10020-022-00471-y] [PMID: 35508978]
[6]
Wu, Y.; Zhao, Y.; Guan, Z. JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties. Cell Adh. Migr., 2024, 18(1), 1-11.
[http://dx.doi.org/10.1080/19336918.2024.2316576]
[7]
Jun, J.; Baek, J.; Yang, S.; Moon, H.; Kim, H.; Cho, H.; Hah, J.M. Discovery of a potent and selective JNK3 inhibitor with neuroprotective effect against amyloid β-induced neurotoxicity in primary rat neurons. Int. J. Mol. Sci., 2021, 22(20), 11084.
[http://dx.doi.org/10.3390/ijms222011084] [PMID: 34681742]
[8]
Wu, Q.; Wu, W.; Jacevic, V. Selective inhibitors for JNK signalling: A potential targeted therapy in cancer. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 574-583.
[http://dx.doi.org/10.1080/14756366.2020.1720013]
[9]
Yao, C.; Shen, Z.; Shen, L.; Kadier, K.; Zhao, J.; Guo, Y.; Xu, L.; Cao, J.; Dong, X.; Yang, B. Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening. Pharmaceuticals, 2023, 16(10), 1459.
[http://dx.doi.org/10.3390/ph16101459] [PMID: 37895928]
[10]
Duong, M.T.H.; Ahn, H.C. Fragment-based and structural investigation for discovery of JNK3 inhibitors. Pharmaceutics, 2022, 14(9), 1900.
[http://dx.doi.org/10.3390/pharmaceutics14091900] [PMID: 36145648]
[11]
Qin, P.; Ran, Y.; Liu, Y.; Wei, C.; Luan, X.; Niu, H.; Peng, J.; Sun, J.; Wu, J. Recent advances of small molecule JNK3 inhibitors for Alzheimer’s disease. Bioorg. Chem., 2022, 128106090.
[http://dx.doi.org/10.1016/j.bioorg.2022.106090] [PMID: 35964505]
[12]
Pai, A. Fingerprint based two-dimensional qsar studies on pyrazolo quinazolines as Cdk2 inhibitors: A rational approach for the design of novel anticancer agents. Indian J. Pharm. Educ. Res., 2019, 53(3s), s299-s312.
[http://dx.doi.org/10.5530/ijper.53.3s.100]
[13]
Bastikar, V.; Bastikar, A.; Gupta, P. Quantitative structure-activity relationship-based computational approaches. In: Computational Approaches for Novel Therapeutic and Diagnostic Designing to Mitigate SARS-CoV-2 Infection; Academic Press, 2022; pp. 191-205.
[http://dx.doi.org/10.1016/B978-0-323-91172-6.00001-7]
[14]
Neves, B.J.; Braga, R.C.; Melo-Filho, C.C.; Moreira-Filho, J.T.; Muratov, E.N.; Andrade, C.H. QSAR-based virtual screening: Advances and applications in drug discovery. Front. Pharmacol., 2018, 9, 1275.
[http://dx.doi.org/10.3389/fphar.2018.01275] [PMID: 30524275]
[15]
Falchi, F.; Bertozzi, S.M.; Ottonello, G.; Ruda, G.F.; Colombano, G.; Fiorelli, C.; Martucci, C.; Bertorelli, R.; Scarpelli, R.; Cavalli, A.; Bandiera, T.; Armirotti, A. Kernel-based, partial least squares quantitative structure-retention relationship model for UPLC retention time prediction: A useful tool for metabolite identification. Anal. Chem., 2016, 88(19), 9510-9517.
[http://dx.doi.org/10.1021/acs.analchem.6b02075] [PMID: 27583774]
[16]
Deokar, H.; Deokar, M.; Buolamwini, J.K. Integration of fingerprint-based similarity searching and kernel-based partial least squares analysis to predict inhibitory activity against CSK, HER2, JAK1, JAK2, and JAK3. Mol. Divers., 2023.
[http://dx.doi.org/10.1007/s11030-022-10596-1] [PMID: 36648693]
[17]
Minh Quang, N.; Tran Thai, H.; Le Thi, H.; Duc Cuong, N.; Hien, N.Q.; Hoang, D.; Ngoc, V.T.B.; Ky Minh, V.; Van Tat, P. Novel thiosemicarbazone quantum dots in the treatment of Alzheimer’s disease combining in silico models using fingerprints and physicochemical descriptors. ACS Omega, 2023, 8(12), 11076-11099.
[http://dx.doi.org/10.1021/acsomega.2c07934] [PMID: 37008140]
[18]
Bai, Y.; Jian, X.; Long, Y. 2006.Kernel partial least-squares regression. The 2006 IEEE International Joint Conference on Neural Network Proceedings, Vancouver, BC, Canada, 16-21 July 2006, pp. 1231-1238.
[19]
Mello-Román, J.D.; Hernandez, A. KPLS optimization approach using genetic algorithms. Procedia Comput. Sci., 2020, 170, 1153-1160.
[http://dx.doi.org/10.1016/j.procs.2020.03.051]
[20]
Bouakouk-Chitti, Z.; Feddal, S.; Meyar, M.; Kellou-Tairi, S. Ligand-based studies on cis-stilbene derivatives as cyclo-oxygenase inhibitors. Med. Chem. Res., 2017, 26(8), 1801-1811.
[http://dx.doi.org/10.1007/s00044-017-1890-1]
[21]
Swahn, B.M.; Huerta, F.; Kallin, E.; Malmström, J.; Weigelt, T.; Viklund, J.; Womack, P.; Xue, Y.; Öhberg, L. Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg. Med. Chem. Lett., 2005, 15(22), 5095-5099.
[http://dx.doi.org/10.1016/j.bmcl.2005.06.083] [PMID: 16140012]
[22]
Swahn, B.M.; Xue, Y.; Arzel, E.; Kallin, E.; Magnus, A.; Plobeck, N.; Viklund, J. Design and synthesis of 2′-anilino-4,4′-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg. Med. Chem. Lett., 2006, 16(5), 1397-1401.
[http://dx.doi.org/10.1016/j.bmcl.2005.11.039] [PMID: 16337120]
[23]
Cao, J.; Gao, H.; Bemis, G.; Salituro, F.; Ledeboer, M.; Harrington, E.; Wilke, S.; Taslimi, P.; Pazhanisamy, S.; Xie, X.; Jacobs, M.; Green, J. Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(10), 2891-2895.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.043] [PMID: 19361991]
[24]
Shin, Y.; Chen, W.; Habel, J.; Duckett, D.; Ling, Y.Y.; Koenig, M.; He, Y.; Vojkovsky, T.; LoGrasso, P.; Kamenecka, T.M. Synthesis and SAR of piperazine amides as novel c-jun N-terminal kinase (JNK) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(12), 3344-3347.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.086] [PMID: 19433357]
[25]
Song, X.; Chen, W.; Lin, L.; Ruiz, C.H.; Cameron, M.D.; Duckett, D.R.; Kamenecka, T.M. Synthesis and SAR of 2-Phenoxypyridines as novel c-Jun N-terminal kinase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(23), 7072-7075.
[http://dx.doi.org/10.1016/j.bmcl.2011.09.090] [PMID: 22004719]
[26]
Zheng, K.; Iqbal, S.; Hernandez, P.; Park, H.; LoGrasso, P.V.; Feng, Y. Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives. J. Med. Chem., 2014, 57(23), 10013-10030.
[http://dx.doi.org/10.1021/jm501256y] [PMID: 25393557]
[27]
He, Y.; Duckett, D.; Chen, W.; Ling, Y.Y.; Cameron, M.D.; Lin, L.; Ruiz, C.H.; LoGrasso, P.V.; Kamenecka, T.M.; Koenig, M. Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(1), 161-164.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.052] [PMID: 24332487]
[28]
Jung, H.; Aman, W.; Hah, J.M. Novel scaffold evolution through combinatorial 3D-QSAR model studies of two types of JNK3 inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(10), 2139-2143.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.063] [PMID: 28372912]
[29]
Rückle, T.; Biamonte, M.; Grippi-Vallotton, T.; Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.; Church, D.J.; Halazy, S.; Jiang, X.; Martinou, I.; Nichols, A.; Sauer, W.; Gotteland, J.P. Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J. Med. Chem., 2004, 47(27), 6921-6934.
[http://dx.doi.org/10.1021/jm031112e] [PMID: 15615541]
[30]
Gaillard, P.; Jeanclaude-Etter, I.; Ardissone, V.; Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.; Church, D.; Cirillo, R.; Gretener, D.; Halazy, S.; Nichols, A.; Szyndralewiez, C.; Vitte, P.A.; Gotteland, J.P. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J. Med. Chem., 2005, 48(14), 4596-4607.
[http://dx.doi.org/10.1021/jm0310986] [PMID: 15999997]
[31]
Zheng, K.; Park, C.M.; Iqbal, S.; Hernandez, P.; Park, H.; LoGrasso, P.V.; Feng, Y. Pyridopyrimidinone derivatives as potent and selective c-Jun N-terminal kinase (JNK) inhibitors. ACS Med. Chem. Lett., 2015, 6(4), 413-418.
[http://dx.doi.org/10.1021/ml500474d] [PMID: 25893042]
[32]
Rajan, R.K.; Ramanathan, M. Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay. J. Comput. Aided Mol. Des., 2020, 34(6), 671-682.
[http://dx.doi.org/10.1007/s10822-020-00297-y] [PMID: 32040807]
[33]
Duan, J.; Dixon, S.L.; Lowrie, J.F.; Sherman, W. Analysis and comparison of 2D fingerprints: Insights into database screening performance using eight fingerprint methods. J. Mol. Graph. Model., 2010, 29(2), 157-170.
[http://dx.doi.org/10.1016/j.jmgm.2010.05.008] [PMID: 20579912]
[34]
Hoffelner, B.S.; Andreev, S.; Plank, N.; Koch, P. Photocaging of pyridinylimidazole-based covalent JNK3 inhibitors affords spatiotemporal control of the binding affinity in live cells. Pharmaceuticals, 2023, 16(2), 264.
[http://dx.doi.org/10.3390/ph16020264] [PMID: 37259409]
[35]
Kulkarni, S.A.; Madhavan, T. Hologram quantitative structure activity relationship analysis of JNK antagonists. J. Chosun Nat. Sci., 2015, 8(2), 81-88.
[http://dx.doi.org/10.13160/ricns.2015.8.2.81]
[36]
Zhang, T.; Inesta-Vaquera, F.; Niepel, M.; Zhang, J.; Ficarro, S.B.; Machleidt, T.; Xie, T.; Marto, J.A.; Kim, N.; Sim, T.; Laughlin, J.D.; Park, H.; LoGrasso, P.V.; Patricelli, M.; Nomanbhoy, T.K.; Sorger, P.K.; Alessi, D.R.; Gray, N.S. Discovery of potent and selective covalent inhibitors of JNK. Chem. Biol., 2012, 19(1), 140-154.
[http://dx.doi.org/10.1016/j.chembiol.2011.11.010] [PMID: 22284361]
[37]
Abu Rabah, R.R.; Sebastian, A.; Vunnam, S.; Sultan, S.; Tarazi, H.; Anbar, H.S.; Shehata, M.K.; Zaraei, S.O.; Elgendy, S.M.; Al Shamma, S.A.; Omar, H.A.; Al-Tel, T.H.; El-Gamal, M.I. Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors. Bioorg. Med. Chem., 2022, 69116894.
[http://dx.doi.org/10.1016/j.bmc.2022.116894] [PMID: 35764033]
[38]
Vaas, S.; Zimmermann, M.O.; Schollmeyer, D.; Stahlecker, J.; Engelhardt, M.U.; Rheinganz, J.; Drotleff, B.; Olfert, M.; Lämmerhofer, M.; Kramer, M.; Stehle, T.; Boeckler, F.M. Principles and applications of CF 2 X moieties as unconventional halogen bond donors in medicinal chemistry, chemical biology, and drug discovery. J. Med. Chem., 2023, 66(15), 10202-10225.
[http://dx.doi.org/10.1021/acs.jmedchem.3c00634] [PMID: 37487500]
[39]
Tandon, N.; Luxami, V.; Kant, D.; Tandon, R.; Paul, K. Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer. RSC Advances, 2021, 11(41), 25228-25257.
[http://dx.doi.org/10.1039/D1RA03979B] [PMID: 35478899]
[40]
El-Gamal, M.I.; Zaraei, S.O.; Madkour, M.M.; Anbar, H.S. Evaluation of substituted pyrazole-based kinase inhibitors in one decade (2011-2020): Current status and future prospects. Molecules, 2022, 27(1), 330.
[http://dx.doi.org/10.3390/molecules27010330] [PMID: 35011562]
[41]
Duong, M.T.H.; Lee, J.H.; Ahn, H.C. C-Jun N-terminal kinase inhibitors: Structural insight into kinase-inhibitor complexes. Comput. Struct. Biotechnol. J., 2020, 18, 1440-1457.
[http://dx.doi.org/10.1016/j.csbj.2020.06.013] [PMID: 32637042]
[42]
Carboni, S.; Hiver, A.; Szyndralewiez, C.; Gaillard, P.; Gotteland, J.P.; Vitte, P.A. AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): A c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J. Pharmacol. Exp. Ther., 2004, 310(1), 25-32.
[http://dx.doi.org/10.1124/jpet.103.064246] [PMID: 14988419]
[43]
Kamenecka, T.; Jiang, R.; Song, X.; Duckett, D.; Chen, W.; Ling, Y.Y.; Habel, J.; Laughlin, J.D.; Chambers, J.; Figuera-Losada, M.; Cameron, M.D.; Lin, L.; Ruiz, C.H.; LoGrasso, P.V. Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J. Med. Chem., 2010, 53(1), 419-431.
[http://dx.doi.org/10.1021/jm901351f] [PMID: 19947601]
[44]
Noël, R.; Shin, Y.; Song, X.; He, Y.; Koenig, M.; Chen, W.; Ling, Y.Y.; Lin, L.; Ruiz, C.H.; LoGrasso, P.; Cameron, M.D.; Duckett, D.R.; Kamenecka, T.M. Synthesis and SAR of 4-(pyrazol-3-yl)-pyridines as novel c-jun N-terminal kinase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(9), 2732-2735.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.104] [PMID: 21185177]
[45]
Hom, R.K.; Bowers, S.; Sealy, J.M.; Truong, A.P.; Probst, G.D.; Neitzel, M.L.; Neitz, R.J.; Fang, L.; Brogley, L.; Wu, J.; Konradi, A.W.; Sham, H.L.; Tóth, G.; Pan, H.; Yao, N.; Artis, D.R.; Quinn, K.; Sauer, J.M.; Powell, K.; Ren, Z.; Bard, F.; Yednock, T.A.; Griswold-Prenner, I. Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK. Bioorg. Med. Chem. Lett., 2010, 20(24), 7303-7307.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.066] [PMID: 21071223]
[46]
Ansideri, F.; Macedo, J.T.; Eitel, M.; El-Gokha, A.; Zinad, D.S.; Scarpellini, C.; Kudolo, M.; Schollmeyer, D.; Boeckler, F.M.; Blaum, B.S.; Laufer, S.A.; Koch, P. Structural optimization of a pyridinylimidazole scaffold: Shifting the selectivity from p38α mitogen-activated protein kinase to c-Jun N-terminal kinase 3. ACS Omega, 2018, 3(7), 7809-7831.
[http://dx.doi.org/10.1021/acsomega.8b00668] [PMID: 30087925]
[47]
Crawford, T.D.; Ndubaku, C.O.; Chen, H.; Boggs, J.W.; Bravo, B.J.; DeLaTorre, K.; Giannetti, A.M.; Gould, S.E.; Harris, S.F.; Magnuson, S.R.; McNamara, E.; Murray, L.J.; Nonomiya, J.; Sambrone, A.; Schmidt, S.; Smyczek, T.; Stanley, M.; Vitorino, P.; Wang, L.; West, K.; Wu, P.; Ye, W. Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization. J. Med. Chem., 2014, 57(8), 3484-3493.
[http://dx.doi.org/10.1021/jm500155b] [PMID: 24673130]
[48]
Tantawy, E.S.; Nafie, M.S.; Morsy, H.A.; El-Sayed, H.A.; Moustafa, A.H.; Mohammed, S.M. Synthesis of novel bioactive pyrido[2,3- d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors. RSC Advances, 2024, 14(16), 11098-11111.
[http://dx.doi.org/10.1039/D4RA00902A] [PMID: 38586446]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 37
Html icon 1
Find your institution