The authors have declared that no competing interests exist.
The aim of this study was to screen the potent phytocompound of
Total nine compounds viz. carandinol, caridone, carrisone, lupeol, p-coumaric acid, gallic acid, rutin, scopoletin and ursolic acid were used for
The qualitative characterization of the extracts showed the presence of a number of phytochemicals such as phenolics, flavonoids, alkaloids, terepnoids, terpenes, steroids, glycosides etc. Carandinol was observed as most effective anti-HIV-1 molecule having lowest binding energy and small inhibition coefficient. Another compound, p-coumaric acid, showed least effectiveness against human immunodeficiency virus- 1 reverse transcriptase or human immunodeficiency virus-1 protease showing highest binding energy and inhibition coefficients among all the evaluated phytocompounds.
The
Human immunodeficiency virus (HIV) is one of the most austere and deadly infectious viruses with disastrous concerns
Reverse transcriptase (RT) is most important enzyme for the retroviruses to complete their life cycle
HIV-1 protease is another key enzyme which is essential for the HIV life-cycle
Various synthetic drugs are in practice against reverse transcriptase such as nucleoside / nucleotide reverse transcriptase inhibitors (Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zidovudine) and non-nucleoside reverse transcriptase inhibitors (NNRTI) (efavirenze, nevirapine, delavirdine and etravirdine). The drugs against HIV-1 protease include saquinavir, ritonavir, indinavir, and nelfinavir. The applications of these synthetic drugs are reported to develop drug resistance in HIV and also the emergence of the new species of the virus
Mature fruits and healthy leaves of
Extracts were prepared using Soxhlet apparatus in different solvents (ethanol, methanol, hexane and double distilled water) by the method described by Singh and Kumari
Total nine phytocompounds of
Compound name | Common name | Pubchem CID no. | Molecular formula | Chemical name (IUPAC name) |
Carindone | Not any | 101316738 |
|
7,7'-bis(2-hydroxypropan-2-yl)-1',4'a,5,9a-tetramethylspiro3a |
Carrisone | Carrison | 5086419 | C15H27O2 | 7-(2-hydroxypropan-2-yl)-1,4a-dimethyl-3,4,5,6,7,8 hexahydronaphthalen-2-one |
Carandinol | Not any | 102202376 |
|
(3R,3aR,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a,13b-hexamethyl-3-propan-2-yl 2,3a,4,5,6,7,7a,9,10,11,11b,12,13,13a-tetradecahydro-1H cyclopentaachrysene-3,9-diol |
Lupeol | Fagarasterol, Clerodol, Monogynol B, | 259846 | C30H50O | 1R,3aR,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a,5a,5b,8,8,11a-hexamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13bhexadecahydrocyclopentaachrysen-9-ol |
Scopoletin | Gelseminic acid | 5280460 | C10H8O4 | 7-hydroxy-6-methoxychromen-2-one |
Ursolic acid | Malol, PrunolUrson, | 64945 | C30H48O3 | (1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl 2,3,4,5,6,6a,7,8,8a,10,11,12, 13, 14b-tetradecahydro-1H-picene-4a-carboxylic acid |
p-caumaric acid | 637542 |
|
(E)-3-(4-hydroxyphenyl)prop-2-enoic acid | |
Rutin | Quercetin 3 Rutinoside | 5280805 |
|
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-(2S3R4S5S6R)oxymethyl]oxan-2 yl]oxychromen-4-one |
Gallic acid | Gallate; Benzoic acid, | 370 |
|
3,4,5-Trihydroxybenzoic acid |
We used hierarchical clustering facility of ChemMine (webserver) ChemMine tools: an online service for analyzing and clustering small molecules (Nucleic Acids Research, 39 (2011) W486-W491) for clustering of all the phyto-compounds. Atom pair structural descriptors and average linkage method were used for the agglomerative hierarchical clustering with tanimoto coefficient as the similarity measure.
The three dimensional structures of HIV reverse transcriptase (PDB ID: 1REV) and HIV protease (PDB ID: 1EBY) were retrieved from protein data bank at resolutions of 2.6 Å and 2.29 Å, respectively
Qualitative characterization of the leaf and fruit extracts showed the presence of various phytocompounds.
Ligands | Binding energy(Kcal/mole) | KI | Intermolecular energy(Kcal/mole) | Internal energy(Kcal/mole) | Torsional energy(Kcal/mole) | Efficiency ranking |
Carandinol | -10.11 | 39.14nM | -11.00 | -0.16 | 0.89 | 1 |
Carindone | -8.85 | 324.25nM | -10.05 | -0.52 | 1.19 | 2 |
Carinsone | -8.71 | 409.19nM | -9.31 | 0.25 | 0.6 | 3 |
Lupeol | -7.54 | 2.97uM | -8.14 | -0.16 | 0.6 | 4 |
Ursolic acid | -7.47 | 3.37uM | -8.36 | 0.33 | 0.89 | 5 |
Gallic acid | -6.58 | 14.94uM | -11.36 | -8.78 | 4.77 | 6 |
p-coumaric acid | -4.64 | 395.5uM | -5.84 | -0.08 | 1.19 | 7 |
Scopoletin | -4.88 | 265.12uM | -5.48 | -0.23 | 0.6 | 8 |
Rutin | -4.41 | 585.02uM | -9.18 | -4.67 | 4.77 | 9 |
KI= Binding affinity index, 1REV= HIV-1 reverse transcriptase
The average linkages have been shown in the hierarchal study of all nine compounds
Molecular docking was performed to analyze the inhibitory action of each phytocompound with both HIV-1 reverse transcriptase (1REV) and HIV-1 protease (1EBY). To find the best binding pose of ligand at the active site of protein, the binding energy was calculated by adding the final intermolecular energy and torsional free energy. Our study revealed that Carandinol, Carindone and Carinsone docked against HIV-1 reverse transcriptase and HIV-1 protease showed maximum binding with binding energy; the values being 10.11, -8.85, -8.71 kcal/mole and -10.99, -9.38 and -7.23 kcal/mole, respectively.
Carnadinol was most effective compound against both 1REV (
Ligands | Binding energy(Kcal/mole) | KI | Intermolecular energy(Kcal/mole) | Internal energy(Kcal/mole) | Torsional energy(Kcal/mole) | Efficiency ranking |
Carandinol | -10.99 | 8.87nM | -11.88 | 0.21 | 0.89 | 1 |
Carindone | -9.38 | 133.79nM | -10.57 | 0.52 | 1.19 | 3 |
Carinsone | -7.23 | 5.0uM | -7.83 | -0.26 | 0.6 | 6 |
Lupeol | -10.24 | 31.14nM | -10.84 | -0.26 | 0.6 | 2 |
Ursolic acid | -8.37 | 738.3nM | -9.26 | 0.07 | 0.89 | 4 |
Gallic acid | -8.01 | 1.35uM | -12.78 | -5.2 | 4.77 | 5 |
p-coumaric acid | -4.7 | 357.15uM | -5.9 | -0.08 | 1.19 | 9 |
Scopoletin | -5.67 | 69.4uM | -6.27 | -0.13 | 0.6 | 8 |
Rutin | -6.28 | 24.76uM | -11.06 | -4.84 | 4.77 | 7 |
KI= Binding affinity index, 1EBY= HIV-1 integrase
The plant extracts of
Carandinol showed the highest inhibition activity and rutin the least inhibition activity against both 1REV and 1 EBY. The inhibition potential of ligand depends upon the active sites of molecules and structure of ligands. Molecular docking was also performed by other worker against HIV-1 RT
From the present study several compounds were screened in the leaf and fruit extracts. In this work, molecular docking was performed by phytocompounds with both HIV-1 reverse transcriptase and HIV-1 protease
RS and BS conceived the idea on subject of research mentioned in the manuscript. RS performed the phytochemical characterization. RS and AN performed the docking study. All the authors have contributed in preparation and editing of the manuscript.
RS is grateful to DST-New Delhi for financial support in the form of N-PDF (PDF/2016/000061). BS is grateful to UPCST-Lucknow for financial support in the form of a research grant.