Topoisomerase I is important for DNA replication and cell division, making it an attractive drug target for anticancer therapy.
A series of indenoisoquinolines displaying potent Top1 inhibitory activity in human renal cell carcinoma cell line SN12C were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated, as well as some measures taken, including region focusing, bootstrapping and the "leave-group-out" cross-validation method. The satisfactory CoMFA model predicted a q2 value of 0.659 and an r2 value of 0.949, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor descriptors, predicted a q2 value of 0.523 and an r2 value of 0.902. The models were graphically interpreted by contour plots which provided insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active anticancer agents.
Written by:
Zhi Y, Yang J, Tian S, Yuan F, Liu Y, Zhang Y, Sun P, Song B, Chen Z. Are you the author?
Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. ; ; ;
Reference: Int J Mol Sci. 2012;13(5):6009-25.
doi: 10.3390/ijms13056009
PubMed Abstract
PMID: 22754346
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