3D-QSAR studies on triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors

Abstract

3D-QSAR studies were carried out on a training set of 53 structurally highly diverse analogues of triclosan to investigate the correlation of the structural properties of triclosan derivatives with the inhibition of the activity of enoyl acyl carrier protein reductase in Plasmodium falciparum (PfENR) by employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The crystal structure bound conformation of triclosan, was used as a template for aligning molecules. The probable binding mode conformations of other inhibitors were explored according to molecular docking and molecular mechanics poisson-boltzmann surface area (MM/PBSA) solvation free energy estimation methods using grid based linear Poisson-Boltzmann calculations. Predictive 3D-QSAR models, established using routine database alignment rule based on crystallographic-bound conformation of template molecule, produced statistically significant results with cross-validated values of 0.64 and 0.54 and non-cross-validated values of 0.96 and 0.97 for CoMFA and CoMSIA models, respectively. The statistically significant models were validated by a test set of nine compounds with predictive r² values of 0.534 and 0.765 for CoMFA and CoMSIA respectively. Our QSAR model is able to successfully explain the geometric and electrostatic complementarities between ligands and receptor and provides useful guidelines to design novel triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors.

Keywords:

• QSAR
• Plasmodium falciparum
• CoMFA
• CoMSIA
• MM/PBSA
• Docking

Acknowledgements

This manuscript is CDRI communication number 7900. This work was supported by the grants from Council of Scientific and Industrial Research (CSIR-India) funded network project NWP0034 (Validation of identified screening models and development of new alternative models for evaluation of new drug entities). PS thanks CSIR for a fellowship.