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Letters in Drug Design & Discovery

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

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Research Article

Identification of Withanolide G as a Potential Inhibitor of Rho-associated Kinase-2 Catalytic Domain to Confer Neuroprotection in Ischemic Stroke

Author(s): Ambarish Kumar Sinha, Kajal Dahiya and Gaurav Kumar*

Volume 20, Issue 7, 2023

Published on: 01 August, 2022

Page: [845 - 853] Pages: 9

DOI: 10.2174/1570180819666220512170331

Price: $65

Abstract

Background: Cerebral stroke is one of the leading causes of death and disability in a large number of patients globally. Brain damage in ischemic stroke is led by a complex cascade of events. The Rho-associated kinase-2 (ROCK2) has a significant role in cerebral vasospasm, vascular remodeling, and inflammation. It is activated in cerebral ischemia and its inhibition leads to a neuroprotective effect.

Objective: The present study is designed to identify potential inhibitors of ROCK2 using a molecular docking approach.

Methods: We docked phytochemicals of Withania somnifera (WS) into the catalytic site of ROCK2 and compared results with inhibitor Y-27632. ADME and drug-likeness properties of WS phytochemicals were also analyzed.

Results: Results suggest that 11 phytochemicals exhibited higher binding affinity toward the ROCK2 catalytic domain compared to the Y-27632 inhibitor. Among these phytochemicals, Withanolide G formed H-bonding and established hydrophobic contacts with key catalytic domain residues of ROCK2.

Conclusion: Our findings suggest that Withanolide G has the potential to inhibit the action of ROCK2 and can be developed as a neurotherapeutic agent to combat cerebral ischemic insult.

Keywords: Rho-associated kinase-2, Withania somnifera, phytochemicals, molecular docking, neuroprotection, ischemic stroke.

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[1]
French, B.R.; Boddepalli, R.S.; Govindarajan, R. Acute ischemic stroke: Current status and future directions. Mo. Med., 2016, 113(6), 480-486.
[PMID: 30228538]
[2]
Kumar, G.; Mukherjee, S.; Paliwal, P.; Singh, S.S.; Birla, H.; Singh, S.P.; Krishnamurthy, S.; Patnaik, R. Neuroprotective effect of chlorogenic acid in global cerebral ischemia-reperfusion rat model. Naunyn Schmiedebergs Arch. Pharmacol., 2019, 392(10), 1293-1309.
[http://dx.doi.org/10.1007/s00210-019-01670-x] [PMID: 31190087]
[3]
Girotra, T.; Lekoubou, A.; Bishu, K.G.; Ovbiagele, B. A contemporary and comprehensive analysis of the costs of stroke in the United States. J. Neurol. Sci., 2020, 410, 116643.
[http://dx.doi.org/10.1016/j.jns.2019.116643] [PMID: 31927342]
[4]
Lecoffre, C.; de Peretti, C.; Gabet, A.; Grimaud, O.; Woimant, F.; Giroud, M.; Béjot, Y.; Olié, V. National trends in patients hospitalized for stroke and stroke mortality in france, 2008 to 2014. Stroke, 2017, 48(11), 2939-2945.
[http://dx.doi.org/10.1161/STROKEAHA.117.017640] [PMID: 28970279]
[5]
Wang, Q.M.; Liao, J.K. ROCKs as immunomodulators of stroke. Expert Opin. Ther. Targets, 2012, 16(10), 1013-1025.
[http://dx.doi.org/10.1517/14728222.2012.715149] [PMID: 22925075]
[6]
Liao, J.K.; Seto, M.; Noma, K. Rho kinase (ROCK) inhibitors. J. Cardiovasc. Pharmacol., 2007, 50(1), 17-24.
[http://dx.doi.org/10.1097/FJC.0b013e318070d1bd] [PMID: 17666911]
[7]
Wang, S.; Chen, C.; Su, K.; Zha, D.; Liang, W.; Hillebrands, J.L.; Goor, H.; Ding, G.; Angiotensin, I.I. Angiotensin II induces reorganization of the actin cytoskeleton and myosin light-chain phosphorylation in podocytes through rho/ROCK-signaling pathway. Ren. Fail., 2016, 38(2), 268-275.
[http://dx.doi.org/10.3109/0886022X.2015.1117896] [PMID: 26652313]
[8]
Liu, L-J.; Yao, F-J.; Lu, G-H.; Xu, C-G.; Xu, Z.; Tang, K.; Cheng, Y-J.; Gao, X-R.; Wu, S-H. The role of the Rho/ROCK pathway in ang II and TGF-β1-induced atrial remodeling. PLoS One, 2016, 11(9), e0161625.
[http://dx.doi.org/10.1371/journal.pone.0161625] [PMID: 27611832]
[9]
Rikitake, Y.; Liao, J.K. ROCKs as therapeutic targets in cardiovascular diseases. Expert Rev. Cardiovasc. Ther., 2005, 3(3), 441-451.
[http://dx.doi.org/10.1586/14779072.3.3.441] [PMID: 15889972]
[10]
Noma, K.; Oyama, N.; Liao, J.K. Physiological role of ROCKs in the cardiovascular system. Am. J. Physiol. Cell Physiol., 2006, 290(3), C661-C668.
[http://dx.doi.org/10.1152/ajpcell.00459.2005] [PMID: 16469861]
[11]
Lee, M-H.; Kundu, J.K.; Chae, J-I.; Shim, J-H. Targeting ROCK/LIMK/cofilin signaling pathway in cancer. Arch. Pharm. Res., 2019, 42(6), 481-491.
[http://dx.doi.org/10.1007/s12272-019-01153-w] [PMID: 31030376]
[12]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055] [PMID: 26852623]
[13]
Kumar, G.P.; Khanum, F. Neuroprotective potential of phytochemicals. Pharmacogn. Rev., 2012, 6(12), 81-90.
[http://dx.doi.org/10.4103/0973-7847.99898] [PMID: 23055633]
[14]
Kumar, G.; Patnaik, R. Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study. Med. Hypotheses, 2016, 92, 35-43.
[http://dx.doi.org/10.1016/j.mehy.2016.04.034] [PMID: 27241252]
[15]
Mirjalili, M.H.; Moyano, E.; Bonfill, M.; Cusido, R.M.; Palazón, J. Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules, 2009, 14(7), 2373-2393.
[http://dx.doi.org/10.3390/molecules14072373] [PMID: 19633611]
[16]
Joshi, V.K.; Joshi, A. Rational use of ashwagandha in ayurveda (Traditional Indian Medicine) for health and healing. J. Ethnopharmacol., 2021, 276, 114101.
[http://dx.doi.org/10.1016/j.jep.2021.114101] [PMID: 33831467]
[17]
Kuboyama, T.; Tohda, C.; Komatsu, K. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases. Biol. Pharm. Bull., 2014, 37(6), 892-897.
[http://dx.doi.org/10.1248/bpb.b14-00022] [PMID: 24882401]
[18]
Mukherjee, S.; Kumar, G.; Patnaik, R.; Withanolide, A. Penetrates brain via intra-nasal administration and exerts neuroprotection in cerebral ischemia reperfusion injury in mice. Xenobiotica, 2019, 1-29.
[http://dx.doi.org/10.1080/00498254.2019.1709228] [PMID: 31870211]
[19]
Kumar, G.; Paliwal, P.; Patnaik, R. Withania somnifera phytochemicals confer neuroprotection by inhibition of the catalytic domain of human matrix metalloproteinase-9. Lett. Drug Des. Discov., 2017, 14(6), 718-726.
[http://dx.doi.org/10.2174/1570180814666161121111811]
[20]
Choudhary, D.; Bhattacharyya, S.; Bose, S. Efficacy and safety of ashwagandha (Withania somnifera (L.) Dunal) root extract in improving memory and cognitive functions. J. Diet. Suppl., 2017, 14(6), 599-612.
[http://dx.doi.org/10.1080/19390211.2017.1284970] [PMID: 28471731]
[21]
Yamaguchi, H.; Miwa, Y.; Kasa, M.; Kitano, K.; Amano, M.; Kaibuchi, K.; Hakoshima, T. Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632. J. Biochem., 2006, 140(3), 305-311.
[http://dx.doi.org/10.1093/jb/mvj172] [PMID: 16891330]
[22]
Kumar, G.; Paliwal, P.; Patnaik, N.; Patnaik, R. Withania somnifera phytochemicals confer neuroprotection by selective inhibition of NNos: An in silico study to search potent and selective inhibitors for human NNOS. J. Theor. Comput. Chem., 2017, 16(5), 1750042.
[http://dx.doi.org/10.1142/S0219633617500420]
[23]
Douche, D.; Sert, Y.; Brandán, S.A.; Kawther, A.A.; Bilmez, B.; Dege, N.; Louzi, A.E.; Bougrin, K.; Karrouchi, K.; Himmi, B. 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol as potential antiviral SARS-CoV-2 candidate: Synthesis, crystal structure, Hirshfeld surface analysis, DFT and molecular docking studies. J. Mol. Struct., 2021, 1232, 130005.
[http://dx.doi.org/10.1016/j.molstruc.2021.130005] [PMID: 33526951]
[24]
Çapan, İ.; Servi, S.; Yıldırım, İ.; Sert, Y. Synthesis, DFT study, molecular docking and drug‐likeness analysis of the new hydrazine‐ 1‐carbothioamide, triazole and thiadiazole derivatives: Potential inhibitors of HSP90. ChemistrySelect, 2021, 6(23), 5838-5846.
[http://dx.doi.org/10.1002/slct.202101086]
[25]
Çapan, İ.; Gümüş, M.; Gökce, H.; Çetin, H.; Sert, Y.; Koca, İ. Synthesis, dielectric properties, molecular docking and ADME studies of pyrrole-3-ones. J. Biomol. Struct. Dyn., 2021, 1-17.
[http://dx.doi.org/10.1080/07391102.2021.1914174] [PMID: 33890547]
[26]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[27]
Mukherjee, S.; Kumar, G.; Patnaik, R. Identification of potential inhibitors of PARP-1, a regulator of caspase-independent cell death pathway, from Withania somnifera phytochemicals for combating neurotoxicity: A structure-based in-silico study. J. Theor. Comput. Chem., 2017, 16(7), 1750062.
[http://dx.doi.org/10.1142/S0219633617500626]
[28]
Yamaguchi, H.; Kasa, M.; Amano, M.; Kaibuchi, K.; Hakoshima, T. Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure, 2006, 14(3), 589-600.
[http://dx.doi.org/10.1016/j.str.2005.11.024] [PMID: 16531242]
[29]
Riento, K.; Ridley, A.J. Rocks: Multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol., 2003, 4(6), 446-456.
[http://dx.doi.org/10.1038/nrm1128] [PMID: 12778124]
[30]
Wang, K.C.; Kim, J.A.; Sivasankaran, R.; Segal, R.; He, Z. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 2002, 420(6911), 74-78.
[http://dx.doi.org/10.1038/nature01176] [PMID: 12422217]
[31]
Liu, B.P.; Strittmatter, S.M. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr. Opin. Cell Biol., 2001, 13(5), 619-626.
[http://dx.doi.org/10.1016/S0955-0674(00)00260-X] [PMID: 11544032]
[32]
Sebbagh, M.; Hamelin, J.; Bertoglio, J.; Solary, E.; Bréard, J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J. Exp. Med., 2005, 201(3), 465-471.
[http://dx.doi.org/10.1084/jem.20031877] [PMID: 15699075]
[33]
Lee, J.H.; Zheng, Y.; von Bornstadt, D.; Wei, Y.; Balcioglu, A.; Daneshmand, A.; Yalcin, N.; Yu, E.; Herisson, F.; Atalay, Y.B.; Kim, M.H.; Ahn, Y-J.; Balkaya, M.; Sweetnam, P.; Schueller, O.; Poyurovsky, M.V.; Kim, H-H.; Lo, E.H.; Furie, K.L.; Ayata, C. Selective ROCK2 inhibition in focal cerebral ischemia. Ann. Clin. Transl. Neurol., 2014, 1(1), 2-14.
[http://dx.doi.org/10.1002/acn3.19] [PMID: 24466563]
[34]
Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol., 2015, 93(5), e393-e395.
[http://dx.doi.org/10.1111/aos.12641] [PMID: 25783615]
[35]
Mueller, B.K.; Mack, H.; Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov., 2005, 4(5), 387-398.
[http://dx.doi.org/10.1038/nrd1719] [PMID: 15864268]
[36]
Impellizzeri, D.; Mazzon, E.; Paterniti, I.; Esposito, E.; Cuzzocrea, S. Effect of fasudil, a selective inhibitor of rho kinase activity, in the secondary injury associated with the experimental model of spinal cord trauma. J. Pharmacol. Exp. Ther., 2012, 343(1), 21-33.
[http://dx.doi.org/10.1124/jpet.111.191239]
[37]
Kumar, S.; Seal, C.J.; Howes, M.J.R.; Kite, G.C.; Okello, E.J. In vitro protective effects of Withania somnifera (L.) dunal root extract against hydrogen peroxide and β-amyloid(1–42)-induced cytotoxicity in differentiated PC12 cells. Phyther. Res., 2010, 24(10), 1567-1574.
[38]
Kumar, G.; Patnaik, R. Inhibition of gelatinases (mmp-2 and mmp-9) by Withania somnifera phytochemicals confers neuroprotection in stroke: An in silico analysis. Interdiscip. Sci., 2017.
[http://dx.doi.org/10.1007/s12539-017-0231-x] [PMID: 28488219]

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