Generic placeholder image

Letters in Drug Design & Discovery


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

Research Article

Docking Study on Caspase 3 Inhibitors As Potential Drugs For Traumatic Brain Cell Apoptosis

Author(s): Sajad Najafi, Abbas Alibakhshi, Karim Mahnam and Javad Ranjbari*

Volume 21, Issue 3, 2024

Published on: 25 October, 2022

Page: [542 - 551] Pages: 10

DOI: 10.2174/1570180819666220915101829

Price: $65


Background: Apoptosis of brain cells (neurons and glia) has a crucial role in humans' pathology of traumatic brain injury (TBI). So, a decrease in the apoptosis rate can potentially reduce the harmful effects and lead to better functional outcomes. Drug repurposing by computational methodologies like protein-ligand docking allows us to make drug discovery more efficient and less expensive.

Objective: In the current study, we used the methodology to study the inhibitory effect of thousands of FDA/non-FDA approved, investigational compounds on caspase 3 as one of the most important members of the cell apoptosis pathway.

Methods: Molecular docking and pharmacokinetic properties calculations were done. The molecular dynamics (MD) simulations of all complexes and free caspase 3 were carried out. We carried out docking experiments using in silico methods and docked a pool of medications to the active site of the human caspase-3 X-ray structure. The best compounds were selected and subjected to pharmacokinetic analysis, molecular simulation, and free energy calculations.

Results: Finally, 6 components (Naldemedine, Celastrol, Nilotinib, Drospirenone, Lumacaftor, and R- 343) were selected as the best in terms of structural and pharmaceutical properties, low toxicity that can be administered orally for the preclinical and clinical future investigations.

Keywords: Caspase 3, apoptosis, virtual screening, docking, MD simulation, MM/PBSA binding free energy.

Graphical Abstract
Kerr, J F R.; Wyllie, A.H.; Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer, 1972, 26(4), 239-257.
[] [PMID: 4561027]
Li, J.; Yuan, J. Caspases in apoptosis and beyond. Oncogene, 2008, 27(48), 6194-6206.
[] [PMID: 18931687]
Cavallucci, V.; D’Amelio, M. Physiological and pathological role of apoptosis. In: Apoptosome; Springer: Dordrecht, 2009; pp. 1-26.
Ghobrial, I.M.; Witzig, T.E.; Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin., 2005, 55(3), 178-194.
[] [PMID: 15890640]
McIlwain, D.R.; Berger, T.; Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol., 2013, 5(4), a008656.
[] [PMID: 23545416]
Nicholson, D.W.; Ali, A.; Thornberry, N.A.; Vaillancourt, J.P.; Ding, C.K.; Gallant, M.; Gareau, Y.; Griffin, P.R.; Labelle, M.; Lazebnik, Y.A.; Munday, N.A.; Raju, S.M.; Smulson, M.E.; Yamin, T-T.; Yu, V.L.; Miller, D.K. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature, 1995, 376(6535), 37-43.
[] [PMID: 7596430]
Zimmermann, K.C.; Green, D.R. How cells die: Apoptosis pathways. J. Allergy Clin. Immunol., 2001, 108(4), S99-S103.
[] [PMID: 11586274]
Slee, E.A.; Adrain, C.; Martin, S.J. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J. Biol. Chem., 2001, 276(10), 7320-7326.
[] [PMID: 11058599]
Porter, A.G.; Jänicke, R.U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ., 1999, 6(2), 99-104.
[] [PMID: 10200555]
Sanchez Mejia, R.O.; Ona, V.O.; Li, M.; Friedlander, R.M. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery, 2001, 48(6), 1393-1401.
[] [PMID: 11383749]
Clausen, F.; Lundqvist, H.; Ekmark, S.; Lewén, A.; Ebendal, T.; Hillered, L. Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. J. Neurotrauma, 2004, 21(9), 1168-1182.
[] [PMID: 15453987]
Clark, R.S.B.; Kochanek, P.M.; Watkins, S.C.; Chen, M.; Dixon, C.E.; Seidberg, N.A.; Melick, J.; Loeffert, J.E.; Nathaniel, P.D.; Jin, K.L.; Graham, S.H. Caspase-3 mediated neuronal death after traumatic brain injury in rats. J. Neurochem., 2000, 74(2), 740-753.
[] [PMID: 10646526]
Thornberry, N.A.; Lazebnik, Y. Caspases: Enemies within. Science, 1998, 281(5381), 1312-1316.
[] [PMID: 9721091]
Wang, K.; Liu, B.; Ma, J. Research progress in traumatic brain penumbra. Chin. Med. J. (Engl.), 2014, 127(10), 1964-1968.
[PMID: 24824264]
Härter, L.; Keel, M.; Hentze, H.; Leist, M.; Ertel, W. Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J. Neuroimmunol., 2001, 121(1-2), 76-78.
[] [PMID: 11730942]
Clark, R.S.B.; Kochanek, P.M.; Chen, M.; Watkins, S.C.; Marion, D.W.; Chen, J.; Hamilton, R.L.; Loeffert, J.E.; Graham, S.H. Increases in Bcl‐2 and cleavage of caspase‐1 and caspase‐3 in human brain after head injury. FASEB J., 1999, 13(8), 813-821.
[] [PMID: 10224225]
Lorente, L.; Martín, M.M.; Argueso, M.; Ramos, L.; Solé-Violán, J.; Riaño-Ruiz, M.; Jiménez, A.; Borreguero-León, J.M. Serum caspase-3 levels and mortality are associated in patients with severe traumatic brain injury. BMC Neurol., 2015, 15(1), 228.
[] [PMID: 26545730]
Li, M.; Ona, V.O.; Chen, M.; Kaul, M.; Tenneti, L.; Zhang, X.; Stieg, P.E.; Lipton, S.A.; Friedlander, R.M. Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience, 2000, 99(2), 333-342.
[] [PMID: 10938439]
Lau, A.; Arundine, M.; Sun, H.S.; Jones, M.; Tymianski, M. Inhibition of caspase-mediated apoptosis by peroxynitrite in traumatic brain injury. J. Neurosci., 2006, 26(45), 11540-11553.
[] [PMID: 17093075]
Yen, T.L.; Chang, C.C.; Chung, C.L.; Ko, W.C.; Yang, C.H.; Hsieh, C.Y. Neuroprotective effects of platonin, a therapeutic immunomodulating medicine, on traumatic brain injury in mice after controlled cortical impact. Int. J. Mol. Sci., 2018, 19(4), 1100.
[] [PMID: 29642394]
Faried, A.; Wiriadisastra, K.; Arifin, M.Z.; Shahib, M.N.; Bisri, T. Inhibition of activated NR2B gene- and caspase-3 protein-expression by glutathione following traumatic brain injury in a rat model. Asian J. Neurosurg., 2011, 6(2), 72-77.
[] [PMID: 22347327]
Li, L.Z.; Bao, Y.J.; Zhao, M. 17Beta-estradiol attenuates programmed cell death in cortical pericontusional zone following traumatic brain injury via upregulation of ERalpha and inhibition of caspase-3 activation. Neurochem. Int., 2011, 58(1), 126-133.
[] [PMID: 21093516]
Hotchkiss, R.S.; Chang, K.C.; Swanson, P.E.; Tinsley, K.W.; Hui, J.J.; Klender, P.; Xanthoudakis, S.; Roy, S.; Black, C.; Grimm, E.; Aspiotis, R.; Han, Y.; Nicholson, D.W.; Karl, I.E. Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte. Nat. Immunol., 2000, 1(6), 496-501.
[] [PMID: 11101871]
Song, F.; Yu, X.; Zhong, T.; Wang, Z.; Meng, X.; Li, Z.; Zhang, S.; Huo, W.; Liu, X.; Zhang, Y.; Zhang, W.; Yu, J. Caspase-3 inhibition attenuates the cytopathic effects of EV71 infection. Front. Microbiol., 2018, 9(817), 817.
[] [PMID: 29755438]
Luo, Y.; Smith, J.V.; Paramasivam, V.; Burdick, A.; Curry, K.J.; Buford, J.P.; Khan, I.; Netzer, W.J.; Xu, H.; Butko, P. Inhibition of amyloid-β aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc. Natl. Acad. Sci. USA, 2002, 99(19), 12197-12202.
[] [PMID: 12213959]
D’Lima, D.; Hermida, J.; Hashimoto, S.; Colwell, C.; Lotz, M. Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum., 2006, 54(6), 1814-1821.
[] [PMID: 16736522]
Flanagan, L.; Meyer, M.; Fay, J.; Curry, S.; Bacon, O.; Duessmann, H. Low levels of Caspase-3 predict favourable response to 5FUbased chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach. Cell Death Dis., 2016, 7(2), e2087-e.
Sharma, S.; Basu, A.; Agrawal, R.K. Pharmacophore modeling and docking studies on some nonpeptide-based caspase-3 inhibitors. BioMed Res. Int., 2013, 2013, 1-15.
[] [PMID: 24089669]
Tavari, M.; Malan, S.F.; Joubert, J. Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors. MedChemComm, 2016, 7(8), 1628-1639.
Wang, Q.; Mach, R.H.; Reichert, D.E. Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors. J. Chem. Inf. Model., 2009, 49(8), 1963-1973.
[] [PMID: 19610597]
Sulpizi, M.; Rothlisberger, U.; Carloni, P. Molecular dynamics studies of caspase-3. Biophys. J., 2003, 84(4), 2207-2215.
[] [PMID: 12668429]
Nicholson, D.W. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ., 1999, 6(11), 1028-1042.
[] [PMID: 10578171]
Clark, A.C. Caspase allostery and conformational selection. Chem. Rev., 2016, 116(11), 6666-6706.
[] [PMID: 26750439]
Fang, B. Structural basis of caspase-3 substrate specificity revealed by crystallography. Enzyme Kinetics, and Computational Modeling; Dissertation, Georgia State University, Georgia, 2009.
Ganesan, R.; Mittl, P.R.E.; Jelakovic, S.; Grütter, M.G. Extended substrate recognition in caspase-3 revealed by high resolution X-ray structure analysis. J. Mol. Biol., 2006, 359(5), 1378-1388.
[] [PMID: 16787777]
Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J. DrugBank: A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res., 2006, 34(90001), D668-D672.
[] [PMID: 16381955]
Sterling, T.; Irwin, J.J. ZINC 15 – Ligand discovery for everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337.
[] [PMID: 26479676]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[] [PMID: 21982300]
Forli, S.; Huey, R.; Pique, M.E.; Sanner, M.F.; Goodsell, D.S.; Olson, A.J. Computational protein–ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc., 2016, 11(5), 905-919.
[] [PMID: 27077332]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol., 2015, 1263, 243-250.
[] [PMID: 25618350]
Schrodinger, L. The PyMOL molecular graphics system., 2010, Version 1.3r1.
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Modeling Environment, Release 2017; Dassault Systèmes: San Diego, 2016.
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[] [PMID: 23092397]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[] [PMID: 28256516]
Güleç, Ö. Türkeş C.; Arslan, M.; Demir, Y.; Yeni, Y.; Hacımüftüoğlu, A.; Ereminsoy, E.; Küfrevioğlu, O.I.; Beydemir, Ş. Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif. Mol. Divers., 2022, 1-21.
[PMID: 35397086]
Yapar, G.; Duran, H.E.; Lolak, N.; Akocak, S.; Turkes, C.; Durgun, M.; Isik, M.; Beydemir, S. Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase. Bioorg. Chem., 2021, 117, 105473.
Akocak, S.; Taslimi, P.; Lolak, N.; Isik, M.; Durgun, M.; Budak, Y.; Turkes, C.; Gulcin, I.; Beydemir, S. Synthesis, characterization, and inhibition study of novel substituted phenylureido sulfaguanidine derivatives as α-glycosidase and cholinesterase inhibitors. Chem. Biodivers., 2021, 18(4), e2000958.
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
[] [PMID: 12612645]
Barkhordari, A.; Mahnam, K.; Mirmohammad-Sadeghi, H. Designing a new bispecific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 using in silico studies for the treatment of rheumatoid arthritis. J. Mol. Model., 2020, 26(9), 1-11.
Kumari, R.; Kumar, R. Consortium, OSDD Lynn AJJoci, modeling. g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model., 2014, 54(7), 1951-62.
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[] [PMID: 25835573]
Massova, I.; Kollman, P.A. Computational alanine scanning to probe protein-protein interactions: A novel approach to evaluate binding free energies. J. Am. Chem. Soc., 1999, 121(36), 8133-8143.
Huo, S.; Massova, I.; Kollman, P.A. Computational alanine scanning of the 1:1 human growth hormone-receptor complex. J. Comput. Chem., 2002, 23(1), 15-27.
[] [PMID: 11913381]

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