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In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent.

Kalani K, Kushwaha V, Sharma P, Verma R, Srivastava M, Khan F, Murthy PK, Srivastava SK - PLoS ONE (2014)

Bottom Line: The selectivity index (SI) of UA for the parasites was found safe.Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug.To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015 (U.P.) India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, 110 001, India.

ABSTRACT
As part of our drug discovery program for anti-filarial agents from Indian medicinal plants, leaves of Eucalyptus tereticornis were chemically investigated, which resulted in the isolation and characterization of an anti-filarial agent, ursolic acid (UA) as a major constituent. Antifilarial activity of UA against the human lymphatic filarial parasite Brugia malayi using in vitro and in vivo assays, and in silico docking search on glutathione-s-transferase (GST) parasitic enzyme were carried out. The UA was lethal to microfilariae (mf; LC100: 50; IC50: 8.84 µM) and female adult worms (LC100: 100; IC50: 35.36 µM) as observed by motility assay; it exerted 86% inhibition in MTT reduction potential of the adult parasites. The selectivity index (SI) of UA for the parasites was found safe. This was supported by the molecular docking studies, which showed adequate docking (LibDock) scores for UA (-8.6) with respect to the standard antifilarial drugs, ivermectin (IVM -8.4) and diethylcarbamazine (DEC-C -4.6) on glutathione-s-transferase enzyme. Further, in silico pharmacokinetic and drug-likeness studies showed that UA possesses drug-like properties. Furthermore, UA was evaluated in vivo in B. malayi-M. coucha model (natural infection), which showed 54% macrofilaricidal activity, 56% female worm sterility and almost unchanged microfilaraemia maintained throughout observation period with no adverse effect on the host. Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug. To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.

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Docking results of studies compounds on B. malayi (Filarial nematode worm) glutathione-S-transferase (BmGST) homology model.(a) docked standard drug DEC-c (control) on BmGST model active site with docking energy −4.9 kcal mol−1, (b) docked another standard drug Ivermectin (control) with docking energy −8.4 kcal mol−1, (c) docked UA on BmGST model with high docking energy −8.6 kcal mol−1.
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pone-0111244-g003: Docking results of studies compounds on B. malayi (Filarial nematode worm) glutathione-S-transferase (BmGST) homology model.(a) docked standard drug DEC-c (control) on BmGST model active site with docking energy −4.9 kcal mol−1, (b) docked another standard drug Ivermectin (control) with docking energy −8.4 kcal mol−1, (c) docked UA on BmGST model with high docking energy −8.6 kcal mol−1.

Mentions: Molecular modeling and geometry cleaning of the UA was performed through ChemBioDraw-Ultra-v12.0 (Cambridge Soft, UK). The 3D structure was subjected to minimized the energy by using molecular mechanics-2 (MM2) force field until the root mean square (RMS) gradient value became smaller than 0.100 kcal mol−1 Å. Re-optimization was done by MOPAC (Molecular Orbital Package) method until the RMS gradient attained a value smaller than 0.0001 kcal mol−1 Å. The 3D chemical structure of known drugs DEC-c (CID:15432) and IVM (CID: 6321424) were retrieved from PubChem compound database (NCBI, USA). The theoretically solved structure of B. malayi glutathione-S-transferase (BmGST) was selected as the potential target for molecular docking simulation studies. The BmGST crystallographic protein 3D structure was retrieved from Protein Data Bank (PDB ID: 1SJO). The Ligsite program was used to identify the potential active site of BmGST model for molecular docking studies and was then cross-checked with template active site as shown in Figure 3[22]. The visualization studies were executed through Discovery Studio v3.5 (Accelrys Inc., USA, 2013).


In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent.

Kalani K, Kushwaha V, Sharma P, Verma R, Srivastava M, Khan F, Murthy PK, Srivastava SK - PLoS ONE (2014)

Docking results of studies compounds on B. malayi (Filarial nematode worm) glutathione-S-transferase (BmGST) homology model.(a) docked standard drug DEC-c (control) on BmGST model active site with docking energy −4.9 kcal mol−1, (b) docked another standard drug Ivermectin (control) with docking energy −8.4 kcal mol−1, (c) docked UA on BmGST model with high docking energy −8.6 kcal mol−1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222910&req=5

pone-0111244-g003: Docking results of studies compounds on B. malayi (Filarial nematode worm) glutathione-S-transferase (BmGST) homology model.(a) docked standard drug DEC-c (control) on BmGST model active site with docking energy −4.9 kcal mol−1, (b) docked another standard drug Ivermectin (control) with docking energy −8.4 kcal mol−1, (c) docked UA on BmGST model with high docking energy −8.6 kcal mol−1.
Mentions: Molecular modeling and geometry cleaning of the UA was performed through ChemBioDraw-Ultra-v12.0 (Cambridge Soft, UK). The 3D structure was subjected to minimized the energy by using molecular mechanics-2 (MM2) force field until the root mean square (RMS) gradient value became smaller than 0.100 kcal mol−1 Å. Re-optimization was done by MOPAC (Molecular Orbital Package) method until the RMS gradient attained a value smaller than 0.0001 kcal mol−1 Å. The 3D chemical structure of known drugs DEC-c (CID:15432) and IVM (CID: 6321424) were retrieved from PubChem compound database (NCBI, USA). The theoretically solved structure of B. malayi glutathione-S-transferase (BmGST) was selected as the potential target for molecular docking simulation studies. The BmGST crystallographic protein 3D structure was retrieved from Protein Data Bank (PDB ID: 1SJO). The Ligsite program was used to identify the potential active site of BmGST model for molecular docking studies and was then cross-checked with template active site as shown in Figure 3[22]. The visualization studies were executed through Discovery Studio v3.5 (Accelrys Inc., USA, 2013).

Bottom Line: The selectivity index (SI) of UA for the parasites was found safe.Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug.To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015 (U.P.) India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, 110 001, India.

ABSTRACT
As part of our drug discovery program for anti-filarial agents from Indian medicinal plants, leaves of Eucalyptus tereticornis were chemically investigated, which resulted in the isolation and characterization of an anti-filarial agent, ursolic acid (UA) as a major constituent. Antifilarial activity of UA against the human lymphatic filarial parasite Brugia malayi using in vitro and in vivo assays, and in silico docking search on glutathione-s-transferase (GST) parasitic enzyme were carried out. The UA was lethal to microfilariae (mf; LC100: 50; IC50: 8.84 µM) and female adult worms (LC100: 100; IC50: 35.36 µM) as observed by motility assay; it exerted 86% inhibition in MTT reduction potential of the adult parasites. The selectivity index (SI) of UA for the parasites was found safe. This was supported by the molecular docking studies, which showed adequate docking (LibDock) scores for UA (-8.6) with respect to the standard antifilarial drugs, ivermectin (IVM -8.4) and diethylcarbamazine (DEC-C -4.6) on glutathione-s-transferase enzyme. Further, in silico pharmacokinetic and drug-likeness studies showed that UA possesses drug-like properties. Furthermore, UA was evaluated in vivo in B. malayi-M. coucha model (natural infection), which showed 54% macrofilaricidal activity, 56% female worm sterility and almost unchanged microfilaraemia maintained throughout observation period with no adverse effect on the host. Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug. To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.

Show MeSH
Related in: MedlinePlus