Docking and QSAR Studies of Camptothecin Derivatives as Inhibitor of DNA Topoisomerase-I

Abstract

AbstractCamptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme Topoisomerase-I (Topo-I) and has shown remarkable anticancer activity in preliminary clinical trials. The major limitation is its low solubility and high adverse reaction. In the studied work, we performed molecular docking of CPT derivatives against Topo-I and developed the quantitative structure activity relationship (QSAR) model for anticancer activity screening. For QSAR, we used CPT and other anticancer drugs with its IC50 values. We used a total of forty seven anticancer drugs as training set and eight compounds as test set and thirty derivatives of CPT as query set. Total of fifty two chemical descriptors were used for the quantitative data calculation. Only four showed good correlation with the experimental activity. Forward feed regression method was used for development of multiple linear regression (MLR) QSAR model. Model showed acceptable regression coefficient (r2) 0.89 (i.e., 89% of correlation) and cross validation coefficient (rCV2) 0.86 (i.e., 86 % of prediction accuracy). After drug likeness test, ten compounds namely, MSB3a, MSB3b, MSB19, MSB22L, MSB22M, MSB22O, MSB22R, MSB25D, MSB37G and MSB39D, showed promising predicted anticancer activity and drug likeness properties. Out of ten, only six compounds namely, MSB19, MSB22L, MSBM, MSB22O, MSB22R and MSB37D indicate two times more activity than the parent CPT compound. In molecular docking studies, all the identified active CPT derivatives showed high binding affinity with Topo-I. QSAR study indicates that connectivity index, electron affinity, mol.wt. & ether group count highly contribute to inhibitory activity of CPT derivatives. These results can offer useful references for directing the molecular design of Topo-I inhibitor with improved anticancer activity.