QSAR, docking and ADMET studies of camptothecin derivatives as inhibitors of DNA topoisomerase‐I

Abstract

In the present work, quantitative structure–activity relationship (QSAR) models of camptothecin derivatives against DNA Topoisomerase‐I (DNA Topo‐I) were developed by multiple linear regression method using leave‐one‐out validation approach. The r2 and rCV2 of the model were 0.89 and 0.86, respectively. The QSAR study indicates that chemical descriptors, namely Connectivity Index (order 1, standard), Electron Affinity (eV), Molecular Weight, Group Count (ether) are correlated well with activity. Further, screening for drug likeness, ADME and toxicity showed that compound CPT9, CPT14, CPT20, CPT21 and CPT22 exhibits marked anticancer activity and possesses two times more potent than standard drug camptothecin. The docking study showed a high binding affinity of predicted active derivatives and showed H‐bond formation with GLY363, ARG364, LYS374, GLN421, ARG488, and ASP‐533 residues, therefore considered as more stable and potent anticancer compounds. The obtained results can be used for the design of novel potent and selective inhibitors of DNA Topo‐I. Copyright © 2013 John Wiley & Sons, Ltd.