in silico Study Reveals Potential Docking Sites of δ 2-isoxazolines derivates for Inhibiting Russell’s Viper PLA2 Toxin
DOI:
https://doi.org/10.11594/jtls.11.01.06Keywords:
δ2-isoxazolines, binding site, Daboia russelli, molecular docking, svPLA2 inhibitorsAbstract
Snake venom phospholipase A2s (svPLA2s) has been known as the most abundant component and predominant cause of Russell’s viper envenomation. Limitation to serum therapy and considerable pharmacological interest led the researcher to synthesized multi-toxic PLA2 inhibitors, δ2-isoxazolines derivate. Although δ2- isoxazolines derivate already proved inhibitor activity in Group II svPLA2 with known IC50, their mechanism of action remains unveiled. Our recent study investigated their inhibitory activity via molecular docking. The virtual screening revealed that the ligand with diverse structures tied to the relatively same active site region. The result sheds light on the significance of His48 and Asp49 as part of the pro-inflammatory eliciting region. ADME analysis was also performed to filter and identify the best potential inhibitor acceptable for human use. This moiety leads to finding a better therapeutic strategy of svPLA2 inhibitors both as an alternative to serum anti-venom treatment.
References
WHO (2016) Guidelines for the management of snakebites. 2nd Edition. India.
Slagboom J, Kool J, Harrison RA, Casewell NR (2017)
Haemotoxic snake venoms: their functional activity,
impact on snakebite victims and pharmaceutical promise. British Journal of Haematology 177(6): 947-959.
doi: 10.1111/bjh.14591.
Gutiérrez JM, Calvete JJ, Habib AG et al. (2017)
Snakebite envenoming. Nature reviews Disease Primers 3 (1): 1-21.
Roly ZY, Hakim MA, Zahan AS et al. (2015) ISOB: A
Database of Indigenous Snake Species of Bangladesh
with respective known venom composition. Bioinformation 11 (2): 107.
Berling I, Isbister GK (2015) Hematologic effects and
complications of snake envenoming. Transfusion medicine Reviews 29 (2): 82 – 89. doi: 10.1016/j.tmrv.
09.005.
Sivaramakrishnan V, Ilamathi M, Ghosh KS et al.
(2016) Virtual analysis of structurally diverse synthetic
analogs as inhibitors of snake venom secretory phospholipase A2. Journal of Molecular Recognition 29 (1):
-32. doi: 10.1002/jmr.2492.
Marcussi S, Sant'Ana CD, Oliveira CZ et al. (2007)
Snake venom phospholipase A2 inhibitors: medicinal
chemistry and therapeutic potential. Current Topics in
Medicinal Chemistry 7 (8): 743-756. doi:
2174/156802607780487614.
Ojeda PG, RamÃrez D, Alzate-Morales J et al. (2018)
Computational studies of snake venom toxins. Toxins 10 (1): 8. doi: 10.3390/toxins10010008.
Tan KY, Tan NH, Tan CH (2018) Venom proteomics
and antivenom neutralization for the Chinese eastern
Russell’s viper, Daboia siamensis from Guangxi and
Taiwan. Scientific Reports 8 (1): 1-14. doi:
1038/s41598-018-25955-y.
Ghag-Sawant M, More TV, Samant LS, Chowdhary AS
(2016) Study of neutralization of enzymatic activity of
Daboia russelii venom by various plant extracts and
their combinations using in vitro methods. International
Journal of Pharmaceutical Sciences and Research 7(6):
doi: 10.13040/IJPSR.0975-8232.7(6)2531-36.
Sakthivel G, Dey A, Nongalleima K et al. (2013) In
vitro and in vivo evaluation of polyherbal formulation
against Russell’s viper and cobra venom and screening
of bioactive components by docking studies. EvidenceBased Complementary and Alternative Medicine 2013.
doi: 10.1155/2013/781216.
Dhananjaya BL, Zameer F, Girish KSD, Souza CJ
(2011) Anti-venom potential of aqueous extract of stem
bark of Mangifera indica L. against Daboia russellii
(Russell’s viper) venom.
Basappa, Kumar MS, Swamy SN et al. (2004) Novel
δ2-isoxazolines as group II phospholipase A2 inhibitors. Bioorganic Medicinal Chemistry Letters 14 (14):
-3681.doi: 10.1016/j.bmcl.2004.05.012.
Tsai IH, Lu PJ, Su JC (1996) Two types of Russell's
viper revealed by variation in phospholipases A2 from
venom of the subspecies. Toxicon 34(1): 99-109.
Robert X, Gouet P (2014) Deciphering key features in
protein structures with the new ENDscript server. Nucleic Acids Research 42 (W1): W320-W324. doi:
1093/nar/gku316.
Tian W, Chen C, Lei X et al. (2018) CASTp 3.0: computed atlas of surface topography of proteins. Nucleic
Acids Research 46 (W1): W363-W367. doi:
1093/nar/gky473.
DeLano WL (2002) Pymol: An open-source molecular
graphics tool. CCP4 Newsletter on Protein Crystallography 40 (1): 82-92.
Singh N, Jabeen T, Pal A et al. (2006) Crystal structures
TN Kholilah, Widodo, N Kurniawan, 2020 / In silico Study Reveals Potential Docking Sites of δ 2-isoxazolines derivates
JTLS | Journal of Tropical Life Science 51 Volume 11 | Number 1 | January | 2021
of the complexes of a group IIA phospholipase A2 with
two natural antiâ€inflammatory agents, anisic acid, and
atropine reveal a similar mode of binding. Proteins:
Structure, Function, and Bioinformatics 64 (1): 89-100.
doi: 10.1002/prot.
Kim S, Chen J, Cheng T, Gindulyte A et al. (2019)
PubChem 2019 update: improved access to chemical
data. Nucleic acids research 47(D1): D1102-D1109.
doi: 10.1093/nar/gky1033.
Backman TW, Cao Y, Girke T (2011) ChemMine tools:
an online service for analyzing and clustering small
molecules. Nucleic acids research 39 (suppl 2): W486-
W491. doi: 10.1093/nar/gkr320.
Trott O, Olson AJ (2010) AutoDock Vina: improving
the speed and accuracy of docking with a new scoring
function, efficient optimization, and multithreading. Journal of Computational Chemistry 31 (2): 455-
doi: 10.1002/jcc.21334.
Stierand K, Rarey M (2010) Drawing the PDB: protein− ligand complexes in two dimensions. ACS Medicinal Chemistry Letters 1 (9): 540-545. doi:
1021/ml100164p.
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand–protein interaction diagrams for drug discovery.
Daina A, Michielin O, Zoete V (2017) SwissADME: a
free web tool to evaluate pharmacokinetics, druglikeness and medicinal chemistry friendliness of small
molecules. Scientific Reports 7: 42717. doi:
1038/srep42717.
Deepa V, Sreekumar S, Biju C (2018) In silico validation of anti-russell’s viper venom activity in Phyllanthus emblica L. and Tamarindus indica L. International Journal of Pharmaceutical Sciences and Drug Research 10 (4): 217 – 226. doi:
25004/IJPSDR.2018.100403.
Apweiler R, Bairoch A, Wu CH et al. (2004) UniProt:
the universal protein knowledgebase. Nucleic Acids
Research 32 (suppl_1): D115 - D119. doi:
1093/nar/gkh131.
Mahmud S, Parves MR, Riza YM et al. (2020) Exploring the potent inhibitors and binding modes of phospholipase A2 through in silico investigation. Journal of Biomolecular Structure and Dynamics 38 (14): 4221-
doi: 10.1080/07391102.2019.1680440.
Kumar JR, Basavarajappa BS, Vishwanath BS, Gowda
TV (2015) Biochemical and pharmacological characterization of three toxic phospholipase A2s from Daboia
russelii snake venom. Comparative Biochemistry and
Physiology Part C: Toxicology Pharmacology 168: 28-
doi: 10.1016/j.cbpc.2014.11.005.
Dennis EA, Cao J, Hsu YH et al. (2011) Phospholipase
A2 enzymes: physical structure, biological function,
disease implication, chemical inhibition, and therapeutic intervention. Chemical Reviews 111 (10): 6130-
Cheng T, Li X, Li Y et al. (2009) Comparative assessment of scoring functions on a diverse test set. Journal
of chemical information and modeling 49 (4): 1079-
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