Quantitative Structure-activity Relationships (QSAR) and Docking Studies on Pyrimidine Derivatives for Antitubercular Activity against M. tuberculosis H37Rv

Aim: QSAR techniques and docking increase the probability of success and reduce time and coast in drug discovery process. The study presents QSAR investigation on 20 pyrimidine derivatives for antitubercular activity against M. tuberculosis.

Materials and Methods: The relationship analysis between compounds and physicochemical properties under study was done by two methods Multiple linear regression (MLR) and Step wise Selection of Terms (SW). The results show good models with six and five (SW) parameters linear equations. While the molecular docking simulation study of selected target Cytochrome P450 14alpha-sterol demethylases (CYP51) of M. tuberculosis H37Rv(1E9X) and ligands (active pyrimidine derivatives) as well as 4-Phenyl-1h-Imidazol for comparison was performed by using Autodock software.

Results: The best model predicted in this study was the eq. 1 (MLR) with excellent statistical fit as SE = 9.06234 R-Sq = 94.9% R-Sq (adj) = 92.1% and F=34.107, while the best model by (SW) was the eq. 2 with excellent statistical fit as SE= 8.89630 R-sq= 94.64% R-sq (adj)= 92.40% F=42.354. All the parameters showed insignificant role in the antitubercular activity. The molecular docking of ligands 3a-j with the cytochrome P450 14alpha-sterol demethylases (CYP51) of M. tuberculosis H37Rv was examined and the best docked pose was shown to have one hydrogen bond with PRO386. While the compound 4-Phenyl-1h-Imidazolshowed lower scores of docker energy.

Conclusion: Quantum chemical calculated parameters can be successfully used in the derived a designer QSAR. And the study indicated that predicted antitubercular activity values for pyrimidine derivative compounds can be modeled by two methods; stepwise (SW) and multiple linear regression (MLR), as well as the docking analysis showed that all compounds exhibited quite similar binding energy and compound 4 as best ligand which showed the highest binding energy and this agreement with experimental data. The most compounds understudy exhibit the best results comparison with the ligand 4-Phenyl-1h-Imidazol.All the rustles could potentially offer a new opportunity in the design of novel properties or extended to other compounds.