Molecular modeling studies of repandusinic acid as potent small molecule for hepatitis B virus through molecular docking and ADME analysis

Abstract

Background: Hepatitis B virus (HBV) has affected over 300 million people worldwide which causes to induce mostly liver disease and liver cancer. It is a member of the family Hepadnaviridae which is a small DNA virus with unusual characters like retroviruses. Generally, hepatoprotective drugs provoke some side effects in human beings. For the reason, this study aims to identify alternative drug molecules from the natural source of medicinal plants with smaller quantity of side effects than those conventional drugs in treating HBV.

Methods: We developed computational methods for calculating drug and target binding resemblance using the Maestro v10.2 of Schrodinger suite. The target and ligand molecules were obtained from recognized databases. Ligand molecules of 40 phytoconstituents were retrieved from variety of plants after we executed crucial analyses such as molecular docking and absorption, distribution, metabolism, and excretion (ADME) analysis.

Results: In the docking analysis, the natural analogues repandusinic acid showed better docking scores of –14.768 with good binding contacts. The remaining bioactive molecules corilagin, furosin, nirurin, iso-quercetin and gallocatechin also showed better docking scores.

Conclusion: This computational analysis reveals that repandusinic acid is a suitable drug candidate for HBV. Therefore, we recommend that this analogue is suitable in further exploration using in vitro studies.

Keywords

hepatitis B virus / phytoconstituents / molecular docking / ADMET analysis

References

[1] Balavignesh, V., Srinivasan, E., Ramesh Babu, N.G. and Saravanan, N. (2013) Molecular docking study ON NS5B polymerase of hepatitis C virus by screening of volatile com-pounds from Acacia concinna and ADMET prediction. Int. J. Pharm. Life Sci. 4, 2548–2558

[2] Vijayakumar, S., Harikrishnan, J. P., Prabhu, S., Morvin Yabesh, J. E. and Manogar, P. (2016) Quantitative ethnobotanical survey of traditional siddha medical practitioners from thiruvarur district with hepatoprotective potentials through in silico methods, Achieve. Life Sci., 10, 11–26

[3] Balavignesh, V., Srinivasan, E., Ramesh Babu, N. G. and Saravanan, N. (2013) Molecular docking study ON NS5B polymerase of hepatitis C virus by screening of volatile compounds from Acacia concinna and ADMET prediction. Int. J. Pharma. Life Sci., 4, 2548–2558

[4] Yang, S., Xing, H., Wang, Q., Wang, X., Liu, S. and Cheng, J. (2016) De novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations resulting from sequential therapy with adefovir dipivoxil, and lamivudine. Ann. Clin. Microbiol. Antimicrob., 15, 24

[5] Zhang, J., Ratanasirintrawoot, S., Chandrasekaran, S., Wu, Z., Ficarro, S. B., Yu, C., Ross, C. A., Cacchiarelli, D., Xia, Q., Seligson, M., (2016) LIN28 regulates stem cell metabolism and conversion to primed pluripotency. Cell Stem Cell, 19, 66–80

[6] Sitterlin, D., Lee, T. H., Prigent, S., Tiollais, P., Butel, J. S. and Transy, C. (1997) Interaction of the UV-damaged DNA-binding protein with hepatitis B virus X protein is conserved among mammalian hepadnaviruses and restricted to transactivation-proficient X-insertion mutants. J. Virol., 71, 6194–6199

[7] Chen, H. S., Kaneko, S., Girones, R., Anderson, R. W., Hornbuckle, W. E., Tennant, B. C., Cote, P. J., Gerin, J. L., Purcell, R. H. and Miller, R. H. (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J. Virol., 67, 1218–1226

[8] Bergametti, F., Bianchi, J. and Transy, C. (2002) Interaction of hepatitis B virus X protein with damaged DNA-binding protein p127: structural analysis and identification of antagonists. J. Biomed. Sci., 9, 706–715

[9] Iftikhar, H., Batool, S., Deep, A., Narasimhan, B., Sharma, P. C. and Malhotra, M. (2017) In silicoanalysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase. Arab. J. Chem., 10, S1267–S1275

[10] Velmurugan, V. and Arunachalam, G. (2014) Comparative molecular docking study of rutin against GABA A type receptor and 4-aminobutyrate-aminotransferase for anti-convulsant activity. J. Chem. Pharm. Res., 9, 974–978

[11] Yunta, M. J. R. (2016) Docking and ligand binding affinity: uses and pitfalls. Ame. J. Model Optimiz., 3, 74–114

[12] Jordan, T. C., Burnett, S. H., Carson, S., Caruso, S. M., Clase, K., DeJong, R. J., Dennehy, J. J., Denver, D. R., Dunbar, D., Elgin, S. C., (2014) A broadly implementable research course in phage discovery and genomics for first-year undergraduate students. MBio, 5, e01051–e13

[13] Patschull, A. O., Gooptu, B., Ashford, P., Daviter, T. and Nobeli, I. (2012) In silico assessment of potential druggable pockets on the surface of a1-antitrypsin conformers. PLoS One, 7, e36612

[14] Mouhssen, L. (2014) Methods to study the phytochemistry and bioactivity of essential oils. Phyto. Res.,18, 35–448

[15] Taylor, L. (2000) Plant Based Drugs and Medicines. Raintree Nutrition Inc., Carson City, 89701

[16] Moreira, J., Klein-Júnior, L. C., Filho, V. C. and de Campos Buzzi, F. (2013) Anti-hyperalgesic activity of corilagin, a tannin isolated from Phyllanthus niruri L. (Euphorbiaceae). J. Ethnopharmacol., 146, 318–323

[17] Duan, W., Yu, Y. and Zhang, L. (2005) Antiatherogenic effects of phyllanthus emblica associated with corilagin and its analogue. Yakugaku Zasshi, 125, 587–591

[18] Chen, Y., Zhang, J., Li, C., Chen, Z. and Jia, L. (2012) Extraction and in vitro antioxidant activity of mopan persimmon polysaccharide. J. Appl. Polym. Sci., 124, 1751–1756

[19] Kinoshita, S., Inoue, Y., Nakama, S., Ichiba, T. and Aniya, Y. (2007) Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. Phytomedicine, 14, 755–762

[20] Hau, D. K., Zhu, G. Y., Leung, A. K., Wong, R. S., Cheng, G. Y., Lai, P. B., Tong, S. W., Lau, F. Y., Chan, K. W., Wong, W. Y., (2010) In vivo anti-tumour activity of corilagin on Hep3B hepatocellular carcinoma. Phytomedicine, 18, 11–15

[21] Zhang, Y. J., Abe, T., Tanaka, T., Yang, C. R. and Kouno, I. (2001) Phyllanemblinins A-F, new ellagitannins from Phyllanthus emblica. J. Nat. Prod., 64, 1527–1532

[22] Kumaran, A. and Karunakaran, R. J. (2006) Nitric oxide radical scavenging active components from Phyllanthus emblica L. Plant Foods Hum. Nutr., 61, 1–5

[23] Huang, Y. L., Chen, C. C., Hsu, F. L. and Chen, C. F. (1998) Tannins, flavonol sulfonates, and a norlignan from Phyllanthus virgatus. J. Nat. Prod., 61, 1194–1197

[24] Miguel, O., Calixto, J., Santos, A., Messana, I., Ferrari, F., Filho, V., Pizzolatti, M. and Yunes, R. (1996) Chemical and preliminary analgesic evaluation of geraniin and furosin isolated from Phyllanthus sellowianus. Planta Med., 62, 146–149

[25] Agyare, C., Lechtenberg, M., Deters, A., Petereit, F. and Hensel, A. (2011) Ellagitannins from Phyllanthus muellerianus (Kuntze) Exell.: Geraniin and furosin stimulate cellular activity, differentiation and collagen synthesis of human skin keratinocytes and dermal fibroblasts. Phytomedicine, 18, 617–624

[26] Subeki, S., Matsuura, H., Takahashi, K., Yamasaki, M., Yamato, O., Maede, Y., Katakura, K., Kobayashi, S., Trimurningsih, T., Chairul, C., (2005) Anti-babesial and anti-plasmodial compounds from Phyllanthus niruri. J. Nat. Prod., 68, 537–539

[27] Murugaiyah, V. and Chan, K. L. (2009) Mechanisms of antihyperuricemic effect of Phyllanthus niruri and its lignan constituents. J. Ethnopharmacol., 124, 233–239

[28] Santos, A. R. S., Filho, V. C., Yunes, R. A. and Calixto, J. B. (1995) Further-studies on the antinociceptive action of the hydroalcoholic extracts from plants of the genus Phyllanthus. J. Pharm. Pharmacol., 47, 66–71

[29] Naik, A. D. and Juvekar, A. R. (2003) Effects of alkaloidal extract of Phyllanthus niruri on HIV replication. Ind. J. Med. Sci., 57, 387–393

[30] Chatterjee, M. and Sil, P. C. (2006) Hepatoprotective effect of aqueous extract of Phyllanthus niruri on nimesulide-induced oxidative stress in vivo. Ind. J. Biochem. Biophys., 43, 299–305

[31] Iizuka, T., Moriyama, H. and Nagai, M. (2006) Vasorelaxant effects of methyl brevifolincarboxylate from the leaves of Phyllanthus niruri. Biol. Pharm. Bull., 29, 177–179

[32] Dhingra, D., Sharma, A. (2006) Antidepressant-like activity of n-hexane extract of nutmeg (Myristica fragrans) seeds in mice. J. Med. Food. 9, 84–92

[33] Venkateswaran, P. S., Millman, I. and Blumberg, B. S. (1987) Effects of an extract from Phyllanthus niruri on hepatitis B and woodchuck hepatitis viruses: in vitro and in vivo studies. Proc. Natl. Acad. Sci. USA, 84, 274–278

[34] Zakaria, M. K., Sankhyan, A., Ali, A., Fatima, K. and Azhar, A. (2014) HBV/HCV infection and inflammation. J. Genet. Syndr. Gene Ther., 5, 241.

[35] Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M. T., Wang, S., Liu, H. and Yin, Y. (2016) Quercetin, inflammation and immunity. Nutrients, 8, 167

[36] Yao, Q. Q. and Zuo, C. X. (1993) Chemical studies on the constituents of Phyllanthus urinaria L. ACTA Pharm. Sin. B, 28, 829–835

[37] Iizuka, T., Nagai, M., Taniguchi, A., Moriyama, H., Hoshi, K. (2005) 125th Annual Meeting of the Pharmaceutical Society of Japan, pp. 134. Tokyo

[38] Vijayakumar, S., Manogar, P., Prabhu, S., Pugazhenthi, M. and Praseetha, P. K. (2019) A pharmacoinformatic approach on cannabinoid receptor 2 (CB2) and different small molecules: Homology modelling, molecular docking, MD simulations, drug designing and ADME analysis. Comput. Biol. Chem., 78, 95–107

[39] Schrödinger, LLC, New York, 2016

[40] Arulmozhi, P., Vijayakumar, S., Praseetha, P. K. and Jayanthi, S. (2019) Extraction methods and computatioinal approaches for evaluation of antimicrobial compounds from Capparis zylanica L. Anal. Biochem., 572, 33–44

[41] Vijayakumar, S., Sathiya, M., Arulmozhi, P., Prabhu, S., Manogar, P., Vinothkannan, R. and Parameswari, N. (2018) Molecular docking and ADME properties of bioactive molecules against human acid-betaglucosidase enzyme, cause of Gaucher’s disease. In silico Pharmacology, 6, 1–11

[42] Prabhu, S., Vijayakumar, S., Manogar, P., Maniam, G. P. and Govindan, N. (2017) Homology modeling and molecular docking studies on type II diabetes complications reduced PPARγ receptor with various ligand molecules. Biomed. Pharmacother., 92, 528–535

[43] SiteMap version 2.3, Schrödinger, LLC, New York, 2016

[44] Glide, 2011, version 5.7, Schrödinger, LLC, New York, 2016

[45] Prime version 3.7, Schrödinger, LLC, New York, 2016

[46] LigPrep. 2011, Version 2.5, Schrödinger, LLC, NewYork, 2016

[47] Mahapatra, R. K., Behera, N. and Naik, P. K. (2012) Molecular modeling and prediction of binding mode and relative binding affinity of Art-Qui-OH with P. falciparum Histo-Aspartic Protease (HAP). Bioinformation, 8, 827–833

[48] QikProp. 2011, version 2.3, Schrödinger, LLC, NewYork, 2016

[49] Morvin Yabesh, J. E., Vijayakumar, S., Arulmozhi, P., Mahadevan, S. and Manogar, P. (2017) Molecular Docking, ADMET Analysis and Dynamics Approach to Potent Natural Inhibitors against Sex Hormone Binding Globulin in Male Infertility. Pharmacogn. J., 6, 35–43

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature