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CONCLUSION

          We
have taken twenty derivatives of an antitubercular agent PA-824 which was
obtained from the literature survey. The structures under investigation were
drawn using the software Marvin sketch. Softwares Power MV and Chem Sketch were
used for physiochemical property calculation. I have used the web based software PASS for the prediction of
biological activity and OSIRIS Property Explorer for the calculation of
molecular properties. All the compounds were further subjected to drug likeness
prediction by Molinspiration and the toxicity were predicted by the software
LAZAR. QSAR and docking studies were applied to understand the druggability of
the PA-824 derivatives. Docking was done using the software Auto Dock.

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              From the biological activities
obtained from PASS, three biological activities were selected- antitubercular,
antibacterial and Antimycobacterial. For all the derivatives antitubercular
activities and antimycobacterial activities were greater than 0.6 and
antibacterial activities were greater than 0.4. There are two compounds,
compounds 1 and 2 showed these three activities greater than the standard
compound PA-824.

               All the compounds including
PA-824 were docked with the protein F420-dependent glucose-6-phosphate
dehydrogenase (3C8N) at the binding site residue HIS40. From the result
obtained from the docking, we got a compound, compound 10 showed highest
binding energy (9.59 Kcal/mol) than that of PA-824(-7.30Kcal/mol). It is clear
that the compound 10 have greater binding affinity to the protein 3C8N than
PA-824. Five compounds, compounds- 8,9,11,16 and 20 showed noticeable binding
affinity than that of PA-824 having binding energies of -8.17 Kcal/mol, -8.43
Kcal/mol, -8.60 Kcal/mol, -7.33 Kcal/mol and -7.90 Kcal/mol respectively.

             Regression was carried out for
QSAR analysis. Regressions were done for three models- Antitubercular,
Antibacterial and Antimycobacterial models and the r2 values
obtained were 0.9066, 0.8964 and 0.9528 respectively. The r2 values
obtained for these three models are near to one and are best models. The
standard errors for these three are very small. So the chosen descriptors are
best to predict the three biological activities for the compounds.

         OSIRIS Property Explorer predicted all
the derivatives as non-toxic and showed the drug likeness score considerably
greater than PA-824 and compounds are fulfilling the optimal requirement for
drug. Compounds 10 and 12 showed considerably high lipophilicity (ClogP) value
(2.94 and 3.16 respectively) than PA-824 (2.81) and most of the compounds have
high solubility value than that of standard. The Bioactivity scores of the
compounds (1-20) are compared with standard compound on the basis of GPCR
ligand, ion channel modulator, nuclear receptor legend, kinase inhibitor,
protease inhibitor, enzyme inhibitor showed that the compounds have good
bioactivity score whose results are in between (-5.0-0.0) showing activeness of
the compound. The drug likenesses of the compounds were also predicted on the
basis of Lipinski’s Rule of Five. The compounds fulfil Lipinski’s rule and show
good drug Likeness score.

         QSAR and docking studies for the
twenty derivatives of the antitubercular agent PA-824 shows that these
compounds have significant bioavailability and docking score. All these
compounds were predicted as non-mutagenic, non – irritant, non-tumorigenic and
have no reproductive effect in toxicity prediction. All compounds were found in
compliance with Lipinski ‘Rule of Five’ and presented a good drug-likeness
score with no violations. It can be lead compounds with antitubercular
activity.           

 

 

          

 

 

 

 

 

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