CoMFA QSAR models of camptothecin analogues based on the distinctive SAR features of combined ABC, CD and E ring substitutions

Quantitative Structure-Activity Relationship (QSAR) paradigm has proved to be useful in understanding the requirements of physicochemical properties of the molecular substituents in many key locations as well as molecules as a whole. The knowledge of Structure-Activity Relationship (SAR), together with the generation of QSAR, constitutes a large body of evidence that may assist in the development of new molecules with excellent biological activity and low toxicity. The camptothecin (CPT) analogues are emerging as a promising group of chemotherapeutic agents. The SAR of these molecules provide insight into the mechanism of topoisomerase I inhibition and help in the synthesis of various CPT analogues by modifying the different rings of the original CPT molecule, giving each analogue a unique property. Here we have demonstrated the Comparative Molecular Force field Analysis (CoMFA) QSAR models for ABC-ring, CD-ring and E-ring substitution of CPT in comparison with the traditional 2D-QSAR model. The 3D-QSAR model gave convincing (standard deviation) r2 values of 0.99, 0.99 and 0.996 as against 2D-QSAR r2 values of 0.83, 0.97 and 0.90 for ABC-Ring, CD-Ring and E-Ring analogues, respectively. In this model special emphasis was given to the contribution of steric and electrostatic force fields in predicting biological activity of CPT derivatives and they were found to improve the QSAR model and make it more precisely predictive.