ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA


Sheema Jb, Waheeta Hopper

Abstract


 

 Objective: Glycogen synthase kinase 3 beta (GSK3β) is one of the main targets for wound healing activity. Our objective is to identify novel inhibitors for GSK3β using in silico approach.

Methods: Grid-based molecular docking, energy-based pharmacophore (e-pharmacophore) modeling, and molecular dynamics (MD) studies were performed for phytocompounds with GSK3β and compared with standard drugs using Schrodinger software.

Results: The glide scores and the molecular interactions of the phytocompounds were well comparable to the standard drugs. The MD was performed for the target bound to the best scoring ligand, entagenic acid. The pharmacophore features of this docked complex were modeled as e-pharmacophore. The constructed e-pharmacophore model was screened against phytocompounds retrieved from literature to identify the ligands with similar pharmacophore features.

Conclusion: The glide scores of fukinolic acid, cimicifugic acid, and linarin were −10.99, −8.28, and −7.25 kcal/mol, respectively. The further 50 nanoseconds MD study determined the stability of GSK3β-linarin complex. Nitrofurazone and sulfathiazole drugs can lead to systemic side effects. Hence, it is concluded that linarin could be a potent wound healing compound against GSK3β.


Keywords


Wound-healing, Glycogen synthase kinase 3 beta, Molecular dynamics, Docking, e-pharmacophore.

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References


Diegelmann RF, Evans MC. Wound healing: An overview of acute,fibrotic and delayed healing. Front Biosci 2004;9:283-9.

Lazarus GS, Cooper DM, Knighton DR, Margolis DJ, Pecoraro RE, Rodeheaver G, et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 1994;130:489-93.

Kumarasamyraja D, Jeganathan NS, Manavalan R. A review on medicinal plants with potential wound healing activity. Int J Pharm Pharm Sci 2012;2:105-11.

Hayouni EA, Miled K, Boubaker S, Bellasfar Z, Abedrabba M, Iwaski H, et al. Hydroalcoholic extract based-ointment from Punica granatum L. Peels with enhanced in vivo healing potential on dermal wounds. Phytomedicine 2011;18:976-84.

Thakur R, Jain N, Pathak R, Sandhu SS. Practices in wound healing studies of plants. Evid Based Complement Alternat Med 2011;2011:438056.

Kumari P, Yadav P, Verma PR, Kumar S, Arya A. A review on wound healing properties of Indian medicinal plants. Indian J Fundam Appl Life Sci 2013;3:220-32.

Paramesha M, Ramesh CK, Krishna V, Swamy HM, Rao SA, Hoskerri J. Effect of dehydroabietylamine in angiogenesis and GSK3-β inhibition during wound healing activity in rats. Med Chem Res 2015;24:295-303.

Zhang DL, Gu LJ, Liu L, Wang CY, Sun BS, Li Z, et al. Effect of wnt signaling pathway on wound healing. Biochem Biophys Res Commun 2009;378:149-51.

Gokhale KM, Tilak BP. Role of glycogen synthase kinase (GSK-3) in Type-2 diabetes and GSK-3 inhibitors as potential anti-diabetics. Int J Pharm Phytopharm Res 2017;3:196-9.

Ahamed KB, Gowdru HB, Rajashekarappa S, Malleshappa KS, Krishna V. Molecular docking of glycogen synthase kinase3-β inhibitor oleanolic acid and its wound-healing activity in rats. Med Chem Res 2013;22:156-64.

Vidya SM, Krishna V, Manjunatha BK, Bharath BR, Rajesh KP, Manjunatha H, et al. Wound healing phytoconstituents from seed kernel of Entada pursaetha DC. and their molecular docking studies with glycogen synthase kinase 3-β. Med Chem Res 2012;21:3195-203.

Harish BG, Krishna V, Santosh Kumar HS, Khadeer Ahamed BM, Sharath R, Kumara Swamy HM, et al. Wound healing activity and docking of glycogen-synthase-kinase-3-beta-protein with isolated triterpenoid lupeol in rats. Phytomedicine 2008;15:763-7.

Nagamani S, Kesavan C, Muthusamy K. E-pharmacophore mapping and docking studies on vitamin D receptor (VDR). Bioinformation 2012;8:705-10.

Tsala DE, Amadou D, Habtemariam S. Natural wound healing and bioactive natural products. Phytopharmacology 2013;4:532-60.

Chen IJ, Foloppe N. Drug-like bioactive structures and conformational coverage with the ligPrep/ConfGen suite: Comparison to programs MOE and catalyst. J Chem Inf Model 2010;50:822-39.

Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M, et al. Epik: A software program for pK(a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 2007;21:681-91.

Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.

Rayalu DJ, Selvaraj C, Singh SK, Ganeshan R, Kumar NU, Seshapani P, et al. Homology modeling, active site prediction, and targeting the anti hypertension activity through molecular docking on endothelin-B receptor domain. Bioinformation 2012;8:81-6.

Gaurav A, Gautam V, Pereira S, Alvarez-Leite J, Vetri F, Choudhury M, et al. Structure-based three-dimensional pharmacophores as an alternative to traditional methodologies. J Receptor Ligand Channel Res 2014;7:27-38.

Tiwari R, Chakraborty S, Dhama K. Miracle of herbs in antibiotic resistant wounds and skin infections: Treasure of nature-a review/perspective. Pharm Sci Monit 2013;4:214-48.

Mensah AY, Sampson J, Houghton PJ, Hylands PJ, Westbrook J, Dunn M, et al. Effects of Buddleja globosa leaf and its constituents relevant to wound healing. J Ethnopharmacol 2001;77:219-26.

Wu F, Bian D, Xia Y, Gong Z, Tan Q, Chen J, et al. Identification of major active ingredients responsible for burn wound healing of Centella asiatica herbs. Evid Based Complement Alternat Med 2012;2012:848093.

Martínez-Vázquez M, Ramírez Apan TO, Aguilar H, Bye R. Analgesic and antipyretic activities of an aqueous extract and of the flavone linarin of Buddleia cordata. Planta Med 1996;62:137-40.

Martínez-Vázquez M, Ramírez Apan TO, Lastra AL, Bye R. A comparative study of the analgesic and anti-inflammatory activities

of Pectolinarin isolated from Cirsium subcoriaceum and linarin isolated from Buddleia cordata. Planta Med 1998;64:134-7.

Mukherjee PK, Maity N, Nema NK, Sarkar BK. Bioactive compounds from natural resources against skin aging. Phytomedicine 2011;19:64-73.

Kusano A, Seyama Y, Nagai M, Shibano M, Kusano G. Effects of fukinolic acid and cimicifugic acids from Cimicifuga species on collagenolytic activity. Biol Pharm Bull 2001;24:1198-201.

Yoo YC, Yoo SK. The effects of compound madecassol on the wound healing. J Korean Soc Plast Reconstr Surg 1998;25:1451-8.

Nafee N, Youssef A, El-Gowelli H, Asem H, Kandil S. Antibiotic-free nanotherapeutics: Hypericin nanoparticles thereof for improved in vitro and in vivo antimicrobial photodynamic therapy and wound healing. Int J Pharm 2013;454:249-58.

Lee TH, Lee GW, Park KH, Mohamed MA, Bang MH, Baek YS, et al. The stimulatory effects of Stewartia koreana extract on the proliferation and migration of fibroblasts and the wound healing activity of the extract in mice. Int J Mol Med 2014;34:145-52.

Nayak BS, Pinto Pereira LM. Catharanthus roseus flower extract has wound-healing activity in sprague dawley rats. BMC Complement Altern Med 2006;6:41.

Swaminathan P, Kalva S, Saleena LM. E-pharmacophore and molecular dynamics study of flavonols and dihydroflavonols as inhibitors against dihydroorotate dehydrogenase. Comb Chem High Throughput Screen 2014;17:663-73.

Sengupta D, Verma D, Naik PK. Docking mode of delvardine and its analogues into the p66 domain of HIV-1 reverse transcriptase: Screening using molecular mechanics-generalized born/surface area and absorption, distribution, metabolism and excretion properties.

J Biosci 2007;32:1307-16.

Schrodinger LL. Small-Molecule Drug Discovery Suite 2013-3: QikProp, version 3.8. New York: Schrodinger, LLC; 2013.

Basha SH, Bethapudi P, Majji Rambabu F. Anti-angiogenesis property by Quercetin compound targeting VEGFR2 elucidated in a computational approach. Eur J Biotechnol Biosci 2014;2:30-46.

Mohindra JK, Rauth AM. Increased cell killing by metronidazole and nitrofurazone of hypoxic compared to aerobic mammalian cells. Cancer Res 1976;36:930-6.

Sulzberger MB, Kanof A, Baer RL, Lowenberg C. Sensitization by topical application of sulfonamides. J Allergy 1947;18:92-103.

Varadharaj V, Kandakatl N. Glycogen synthase kinase-3 beta protein inhibition by selected phytocompounds in silico. Asian J Pharm Clin Res 2016;10:87-90.

Aparna VA, Mohanalakshmi NA, Dineshkumar KE, Hopper WA. Identification of inhibitors for RND efflux pump of Pseudomonas aeruginosa using structurebased pharmacophore modeling approach. Int J Pharm Pharm Sci 2014;6:84-9.

Daisy P, Vijayalakshmi P, Selvaraj C, Singh SK, Saipriya K. Targeting multidrug resistant mycobacterium tuberculosis htrA2 with identical chemical entities of fluoroquinolones. Indian J Pharm Sci 2012;74:217-22.

Cespedes CL, Sampietro DA, Seigler DS, Rai M, editors. Natural Antioxidants and Biocides from Wild Medicinal Plants. Oxford, UK: CABI; 2013.

Han S, Sung KH, Yim D, Lee S, Lee CK, Ha NJ, et al. The effect of linarin on lps-lnduced cytokine production and nitric oxide inhibition in murine macrophages cell line RAW264. 7. Arch Pharm Res 2002;25:170-7.




About this article

Title

ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA

Topics

BIOTECHNOLOGY

Keywords

Wound-healing, Glycogen synthase kinase 3 beta, Molecular dynamics, Docking, e-pharmacophore.

DOI

10.22159/ajpcr.2018.v11i2.22962

Date

01-02-2018

Additional Links

Manuscript Submission

Journal

Asian Journal of Pharmaceutical and Clinical Research
Vol 11 Issue 2 February 2018 Page: 181-188

Print ISSN

0974-2441

Online ISSN

2455-3891

Authors & Affiliations

Sheema Jb
Department of Biotechnology, Faculty of Engineering and Technology, SRM University, Kattankulathur, Chennai - 603 203,Tamil Nadu, India.
India

Waheeta Hopper
Department of Biotechnology, Faculty of Engineering and Technology, SRM University, Kattankulathur, Chennai - 603 203,Tamil Nadu, India.
India


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