Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Back
Research Article

Computational Study Reveals PARP1 and P2Y1 Receptors as Prospective Targets of Withaferin-A for Cardiovascular Diseases

Author(s): Rekha Ravindran, Praveen Kumar Posa Krishnamoorthy*, Sriram Kumar, Sujata Roy, Sakthi Abirami Gowthaman and Johanna Rajkumar

Volume 19, Issue 4, 2022

Published on: 21 January, 2022

Page: [323 - 336] Pages: 14

DOI: 10.2174/1570180819666211228103102

Price: $65

Abstract

Background: Cardiovascular Diseases (CVDs) remain the leading cause of death worldwide, which urges for effective strategies of prevention and treatment. Withaferin-A (WFA), the key metabolite identified in Withania somnifera, has been known for its cardioprotective properties. Although it has been traditionally employed to treat cardiovascular ailments for several decades, its exact mechanism of action still remains unexplained.

Objective: The current study modeled and scored the interactions of WFA with nine prospective protein targets associated with cardiovascular diseases through molecular docking and DSX-scoring.

Methods: Molecular docking was carried out using Autodock and DSX scoring was carried out using DSX standalone software. WFA was observed to favorably interact with six targets before DSX-based rescoring, but only with Poly (ADP-Ribose) Polymerase-1 and P2Y Purinoceptor-1 after DSX-based rescoring. The spatial orientation, physicochemical properties and structural features of Withaferin-A were compared with that of the approved drugs by pharmacophore modeling and hierarchical clustering.

Results: The results of molecular docking, DSX-based rescoring and complete pharmacophore modeling together revealed that PARP1 and P2Y1 receptors could be prospective targets of WFA for the treatment of CVD.

Conclusion: Simulation using GROMACS has revealed that WFA forms a more stable complex with PARP1 and will be useful in developing broad-spectrum drugs against cardiovascular diseases. Further computational studies through machine learning and network pharmacology methods can be carried out to improve the Withaferin-A compound features by incorporating additional functional groups necessary for molecular recognition of the target genes in the network responsible for cardiovascular diseases.

Keywords: Cardiovascular diseases, Withania somnifera, Withaferin-A, molecular docking, DSX scoring, PARP1.

« Previous Next »
Graphical Abstract

[1]
Aje, T.O.; Miller, M. Cardiovascular disease: A global problem extending into the developing world. World J. Cardiol., 2009, 1(1), 3-10.
[http://dx.doi.org/10.4330/wjc.v1.i1.3] [PMID: 21160570]
[2]
Flordellis, C.; Papathanasopoulos, P.; Lymperopoulos, A.; Matsoukas, J.; Paris, H. Emerging therapeutic approaches multi-targeting receptor tyrosine kinases and g protein-coupled receptors in cardiovascular disease. Cardiovasc. Hematol. Agents Med. Chem., 2007, 5(2), 133-145.
[http://dx.doi.org/10.2174/187152507780363188] [PMID: 17430136]
[3]
Pal, S.K.; Shukla, Y. Herbal medicine: Current status and the future. Asian Pac. J. Cancer Prev., 2003, 4(4), 281-288.
[PMID: 14728584]
[4]
Matsuda, H.; Murakami, T.; Kishi, A.; Yoshikawa, M. Structures of withanosides I, II, III, IV, V, VI, and VII, new withanolide glycosides, from the roots of Indian Withania somnifera DUNAL. and inhibitory activity for tachyphylaxis to clonidine in isolated guinea-pig ileum. Bioorg. Med. Chem., 2001, 9(6), 1499-1507.
[http://dx.doi.org/10.1016/S0968-0896(01)00024-4] [PMID: 11408168]
[5]
Ravindran, R.; Sharma, N.; Roy, S.; Thakur, A.R.; Ganesh, S.; Kumar, S.; Devi, J.; Rajkumar, J. Interaction studies of Withania somnifera’s key metabolite Withaferin a with different receptors associated with cardiovascular disease. Curr. Computeraided Drug Des., 2015, 11(3), 212-221.
[http://dx.doi.org/10.2174/1573409912666151106115848] [PMID: 26548552]
[6]
Martorana, F.; Guidotti, G.; Brambilla, L.; Rossi, D. Withaferin A inhibits nuclear factor-κB-dependent pro-inflammatory and stress response pathways in the astrocytes. Neural Plast., 2015, 2015381964
[http://dx.doi.org/10.1155/2015/381964] [PMID: 26266054]
[7]
Mishra, L.C.; Singh, B.B.; Dagenais, S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): A review. Altern. Med. Rev., 2000, 5(4), 334-346.
[PMID: 10956379]
[8]
Vanden Berghe, W.; Sabbe, L.; Kaileh, M.; Haegeman, G.; Heyninck, K. Molecular insight in the multifunctional activities of Withaferin A. Biochem. Pharmacol., 2012, 84(10), 1282-1291.
[http://dx.doi.org/10.1016/j.bcp.2012.08.027] [PMID: 22981382]
[9]
Yu, Y.; Hamza, A.; Zhang, T.; Gu, M.; Zou, P.; Newman, B.; Li, Y.; Gunatilaka, A.A.; Zhan, C.G.; Sun, D. Withaferin a targets heat shock protein 90 in pancreatic cancer cells. Biochem. Pharmacol., 2010, 79(4), 542-551.
[http://dx.doi.org/10.1016/j.bcp.2009.09.017] [PMID: 19769945]
[10]
Mohan, R.; Hammers, H.J.; Bargagna-Mohan, P.; Zhan, X.H.; Herbstritt, C.J.; Ruiz, A.; Zhang, L.; Hanson, A.D.; Conner, B.P.; Rougas, J.; Pribluda, V.S. Withaferin a is a potent inhibitor of angiogenesis. Angiogenesis, 2004, 7(2), 115-122.
[http://dx.doi.org/10.1007/s10456-004-1026-3] [PMID: 15516832]
[11]
Patel, S.B.; Rao, N.J.; Hingorani, L.L. Safety assessment of Withania somnifera extract standardized for Withaferin A: Acute and sub-acute toxicity study. J. Ayurveda Integr. Med., 2016, 7(1), 30-37.
[http://dx.doi.org/10.1016/j.jaim.2015.08.001] [PMID: 27297507]
[12]
Zheng, C.J.; Han, L.Y.; Yap, C.W.; Ji, Z.L.; Cao, Z.W.; Chen, Y.Z. Therapeutic targets: Progress of their exploration and investigation of their characteristics. Pharmacol. Rev., 2006, 58(2), 259-279.
[http://dx.doi.org/10.1124/pr.58.2.4] [PMID: 16714488]
[13]
Stafforini, D.M. Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc. Drugs Ther., 2009, 23(1), 73-83.
[http://dx.doi.org/10.1007/s10557-008-6133-8] [PMID: 18949548]
[14]
Jin, J.; Daniel, J.L.; Kunapuli, S.P. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J. Biol. Chem., 1998, 273(4), 2030-2034.
[http://dx.doi.org/10.1074/jbc.273.4.2030] [PMID: 9442040]
[15]
Ntambi, J.M.; Miyazaki, M.; Stoehr, J.P.; Lan, H.; Kendziorski, C.M.; Yandell, B.S.; Song, Y.; Cohen, P.; Friedman, J.M.; Attie, A.D. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc. Natl. Acad. Sci. USA, 2002, 99(17), 11482-11486.
[http://dx.doi.org/10.1073/pnas.132384699] [PMID: 12177411]
[16]
Wang, H.; Klein, M.G.; Zou, H.; Lane, W.; Snell, G.; Levin, I.; Li, K.; Sang, B.C. Crystal structure of human stearoyl-coenzyme a desaturase in complex with substrate. Nat. Struct. Mol. Biol., 2015, 22(7), 581-585.
[http://dx.doi.org/10.1038/nsmb.3049] [PMID: 26098317]
[17]
Pacher, P.; Szabó, C. Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: The therapeutic potential of PARP inhibitors. Cardiovasc. Drug Rev., 2007, 25(3), 235-260.
[http://dx.doi.org/10.1111/j.1527-3466.2007.00018.x] [PMID: 17919258]
[18]
Ogletree, M.L.; Allen, G.T. Interspecies differences in thromboxane receptors: Studies with thromboxane receptor antagonists in rat and guinea pig smooth muscles. J. Pharmacol. Exp. Ther., 1992, 260(2), 789-794.
[PMID: 1531361]
[19]
Funk, C.D. Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat. Rev. Drug Discov., 2005, 4(8), 664-672.
[http://dx.doi.org/10.1038/nrd1796] [PMID: 16041318]
[20]
Ouvrard-Pascaud, A.; Sainte-Marie, Y.; Bénitah, J.P.; Perrier, R.; Soukaseum, C.; Nguyen Dinh Cat, A.; Royer, A.; Le Quang, K.; Charpentier, F.; Demolombe, S.; Mechta-Grigoriou, F.; Beggah, A.T.; Maison-Blanche, P.; Oblin, M.E.; Delcayre, C.; Fishman, G.I.; Farman, N.; Escoubet, B.; Jaisser, F. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation, 2005, 111(23), 3025-3033.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.503706] [PMID: 15939817]
[21]
Borissoff, J.I.; Spronk, H.M.; Heeneman, S.; ten Cate, H. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze? Cardiovasc. Res., 2009, 82(3), 392-403.
[http://dx.doi.org/10.1093/cvr/cvp066] [PMID: 19228706]
[22]
Dolinsky, T.J.; Nielsen, J.E.; McCammon, J.A.; Baker, N.A. 2004.
[23]
Sadowski, J.; Gasteiger, J.; Klebe, G. Comparison of automatic three-dimensional model builders using 639 X-ray structures. J. Chem. Inf. Comput. Sci., 1994, 34(4), 1000-1008.
[http://dx.doi.org/10.1021/ci00020a039]
[24]
Trott, O.; Olson, A.J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[25]
Sayle, R.A.; Milner-White, E.J. RASMOL: Biomolecular graphics for all. Trends Biochem. Sci., 1995, 20(9), 374-376.
[http://dx.doi.org/10.1016/S0968-0004(00)89080-5] [PMID: 7482707]
[26]
Neudert, G.; Klebe, G. DSX: A knowledge-based scoring function for the assessment of protein-ligand complexes. J. Chem. Inf. Model., 2011, 51(10), 2731-2745.
[http://dx.doi.org/10.1021/ci200274q] [PMID: 21863864]
[27]
Tiwari, A.; Panigrahi, S.K. HBAT: A complete package for analysing strong and weak hydrogen bonds in macromolecular crystal structures. In Silico Biol., 2007, 7(6), 651-661.
[PMID: 18467777]
[28]
Horowitz, S.; Trievel, R.C. Carbon-oxygen hydrogen bonding in biological structure and function. J. Biol. Chem., 2012, 287(50), 41576-41582.
[http://dx.doi.org/10.1074/jbc.R112.418574] [PMID: 23048026]
[29]
DeLano, W.L. 2002.
[30]
Schneidman-Duhovny, D.; Dror, O.; Inbar, Y.; Nussinov, R.; Wolfson, H.J. Deterministic pharmacophore detection via multiple flexible alignment of drug-like molecules. J. Comput. Biol., 2008, 15(7), 737-754.
[http://dx.doi.org/10.1089/cmb.2007.0130] [PMID: 18662104]
[31]
Praveen Kumar, P.K. Sekar, Subasree; Udhayachadran, Arthi; Mobashir, Imam; Chirag, Gowda; Prasanna, D Revanasiddappa T-cell epitope-based vaccine design against nipah virus by reverse vaccinology approach. Comb. Chem. High Throughput Screen., 2020, 23(8), 788-796.
[http://dx.doi.org/10.2174/1386207323666200427114343] [PMID: 32338213]
[32]
Gangadharappa, B.S.; Sharath, R.; Revanasidappa, P.D.; Chandramohan, V.; Balasubraniam, M.; Vardhineni, T.P. Structural insights of metallo-beta-lactamase revealed an effective way of inhibition of enzyme by natural inhibitors. J. Biomol. Struct. Dyn., 2019, 38(13), 3757-3771.
[http://dx.doi.org/10.1080/07391102.2019.1667265] [PMID: 31514687]
[33]
Kell, P.J.; Creer, M.H.; Crown, K.N.; Wirsig, K.; McHowat, J. Inhibition of platelet-activating factor (PAF) acetylhydrolase by methyl arachidonyl fluorophosphonate potentiates PAF synthesis in thrombin-stimulated human coronary artery endothelial cells. J. Pharmacol. Exp. Ther., 2003, 307(3), 1163-1170.
[http://dx.doi.org/10.1124/jpet.103.055392] [PMID: 14560038]
[34]
Hechler, B.; Nonne, C.; Roh, E.J.; Cattaneo, M.; Cazenave, J.P.; Lanza, F.; Jacobson, K.A.; Gachet, C. MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2¢-deoxyadenosine-3¢,5¢-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice. J. Pharmacol. Exp. Ther., 2006, 316(2), 556-563.
[http://dx.doi.org/10.1124/jpet.105.094037] [PMID: 16236815]
[35]
Rifkin, R.A.; Maggio, E.T.; Dike, S.; Kerr, D.A.; Levy, M. n-Dodecyl-β-D-maltoside inhibits aggregation of human interferon-β-1b and reduces its immunogenicity. J. Neuroimmune Pharmacol., 2011, 6(1), 158-162.
[http://dx.doi.org/10.1007/s11481-010-9226-7] [PMID: 20532646]
[36]
Herceg, Z.; Wang, Z.Q. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat. Res., 2001, 477(1-2), 97-110.
[http://dx.doi.org/10.1016/S0027-5107(01)00111-7] [PMID: 11376691]
[37]
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol., 2011, 31(5), 986-1000.
[http://dx.doi.org/10.1161/ATVBAHA.110.207449] [PMID: 21508345]
[38]
Serhan, C.N.; Chiang, N.; Dalli, J.; Levy, B.D. Lipid mediators in the resolution of inflammation. Cold Spring Harb. Perspect. Biol., 2014, 7(2)a016311
[http://dx.doi.org/10.1101/cshperspect.a016311] [PMID: 25359497]
[39]
Cannon, M.V.; van Gilst, W.H.; de Boer, R.A. Emerging role of liver X receptors in cardiac pathophysiology and heart failure. Basic Res. Cardiol., 2016, 111(1), 3.
[http://dx.doi.org/10.1007/s00395-015-0520-7] [PMID: 26611207]
[40]
Fan, Y.S.; Eddy, R.L.; Byers, M.G.; Haley, L.L.; Henry, W.M.; Nowak, N.J.; Shows, T.B. The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2. Cytogenet. Cell Genet., 1989, 52(1-2), 83-84.
[http://dx.doi.org/10.1159/000132846] [PMID: 2558856]
[41]
Taddei, S.; Virdis, A.; Ghiadoni, L.; Salvetti, G.; Bernini, G.; Magagna, A.; Salvetti, A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension, 2001, 38(2), 274-279.
[http://dx.doi.org/10.1161/01.HYP.38.2.274] [PMID: 11509489]
[42]
Warren, G.L.; Andrews, C.W.; Capelli, A.M.; Clarke, B.; LaLonde, J.; Lambert, M.H.; Lindvall, M.; Nevins, N.; Semus, S.F.; Senger, S.; Tedesco, G.; Wall, I.D.; Woolven, J.M.; Peishoff, C.E.; Head, M.S. A critical assessment of docking programs and scoring functions. J. Med. Chem., 2006, 49(20), 5912-5931.
[http://dx.doi.org/10.1021/jm050362n] [PMID: 17004707]
[43]
Wermuth, C.G.; Ganellin, C.R.; Lindberg, P.; Mitscher, L.A. Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998). Pure and Applied Chemistry. Chimie Pure et Appliquee, 1998, 70(5), 1129-1143.
[http://dx.doi.org/10.1351/pac199870051129]
[44]
Ku, S.K.; Bae, J.S. Antiplatelet, anticoagulant, and profibrinolytic activities of withaferin A. Vascul. Pharmacol., 2014, 60(3), 120-126.
[http://dx.doi.org/10.1016/j.vph.2014.01.009] [PMID: 24534482]

Rights & Permissions Print Cite
Article Metrics
17
1
© 2025 Bentham Science Publishers | Privacy Policy