A Structure Guided QSAR: A Rapid and Accurate technique to predict IC₅₀: A Case Study

E-ISSN： 1875-6697|11|2|152-163

ISSN： 1573-4099

Source： Current Computer - Aided Drug Design, Vol.11, Iss.2, 2015-09, pp. : 152-163

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Abstract

In this study, the role of highly structured water molecules present in the active site of theleukotriene A4 hydrolase (LTA4H) enzyme has been critically examined through the dockingexperiments. It was observed that different experiments were necessary to perform the dockingstudies. The ligands capable of displacing or interacting with bound-water(s) displayed differentbinding poses as well as the scores. The docking scores E (CvdW) from Glide and ChemScore (CS)from FlexX, with and without bound-waters, obtained through different docking experiments were used to construct twostructure guided bi-parametric linear regression models using the IClt;subgt;50lt;/subgt; enzyme activity data. The predictive squaredcorrelation coefficients (Qlt;supgt;2lt;/supgt;) obtained for these models, with and without bound waters, were found to be 0.73 and 0.67,respectively. These models were validated using test and validated sets of compounds. Utilizing these QSAR models, 409proposed structures were docked and their respective predicted IClt;subgt;50lt;/subgt; data were generated. From the in-silico evaluation ofthese 409 proposed structures representing diverse chemotypes, 39 compounds were triaged, synthesized and evaluated inthe enzyme inhibition assay. The predicted and experimental biological data (IClt;subgt;50lt;/subgt;) was correlated and the square of thecorrelation coefficient (Rlt;supgt;2lt;/supgt;) between the observed and calculated IClt;subgt;50lt;/subgt; was found to be 0.87.