3D-QSAR studies of triazolopyrimidine derivatives of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis> dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics,docking, and genetic algorithm-based methods |
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Authors: | Priyanka Shah Sumit Kumar Sunita Tiwari Mohammad Imran Siddiqi |
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Institution: | (1) Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow, 226 001, India;(2) National Institute of Pharmaceutical Education and Research, Raebareli, UP, India;(3) Department of Physiology, C.S.M.M.U., Lucknow, UP, India; |
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Abstract: | A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking
and 3D quantitative structure–activity relationship studies. Genetic algorithm-based criteria was adopted for selection of
training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model
development and validation. Both the comparative molecular field analyses (
q\textLOO2 = 0.841 q_{\text{LOO}}^2 = 0.{841} ,
r\textncv2 = 0.99 r_{\text{ncv}}^2 = 0.{99} ) and comparative molecular similarity indices analyses (
q\textLOO2 = 0.757 q_{\text{LOO}}^2 = 0.{757} ,
r\textncv2 = 0.943 r_{\text{ncv}}^2 = 0.{943} ) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore
the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based
on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules
and will assist in the design of more potent inhibitors of PfDHODH. |
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Keywords: | QSAR Genetic algorithm-based feature selection hierarchical clustering and docking Molecular dynamics |
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