Pharmacophore based screening and QSAR analysis of structurally diverse compounds for lead selection and optimization against multiple targets

N.S. Hari Narayana Moorthy, Maria J. Ramos and Pedro A. Fernandes, University of Porto, Portugal

Structurally diverse molecules possessed α-glucosidase, RNR, FTase and hERG inhibitory activities were considered for the present lead analysis studies. The bioactive conformers derived from the pharmacophore based conformer (PBC) search method were used for the QSAR analysis. The flexialigned structure of the active compounds in the series and the reference compounds were considered as the query pharmacophore structures. The developed QSAR models were validated by various validation methods (LMO, LOO, LSO, bootstrapping, Y-randomization and test set). The statistical parameters calculated for the models show that the developed models are statistically significant and have predicted the activities with small residual errors. The crossvalidated correlation coefficient (Q2) values obtained from different validation methods show >0.7. Other correlations coefficient and statistical parameters show that the developed models are reliable and robust. In order to reduce the toxicity especially the hERG blocking activity of the compounds, the bioactive conformers developed through the PBC were filtered through the query pharmacophore of hERG inhibitors. The bioactive pharmacophoric conformers were also used for the docking analysis on the targets. The results obtained from the studies suggest that the vdW surface property of the molecules is important for the activity. The flexibility bonds and the presence of aromatic rings have better activity against the targets. This study results and the ongoing research in our laboratory were used to develop novel lead molecules. It can be a better drug designing with the consideration of the pharmacodynamic and pharmacokinetic compatibility of the molecules/lead to improve the success rate of the molecules. 

References
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