2D- and 3D-QSAR Studies on 54 Anti-tumor Rubiaceae-type Cyclopeptides

RA-VII, a bicyclic hexapeptide isolated from the roots of Rubia cordifolia, Rubia akane belongs to Rubiaceae-type cyclopeptides (RAs) and has attracted much attention for its potent anti-tumor activity and its bicyclic structure incorporating the isodityrosine moiety. In this work, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methods were employed to develop 2D- and 3D-QSAR models for 54 anti-tumor RAs. The LOO cross-validated q2 values of HQSAR, CoMFA and CoMSIA models are 0.701, 0.510 and 0.613, respectively. The predictive ability of these models was validated by the test set including 7 RAs, and the predicted IC50 values were in good agreement with the experimental IC50 values. HQSAR result showed that chirality descriptor plays an important role in anti-tumor activity of RAs and OMe at R1 and R2 is necessary for increasing their activity. CoMFA and CoMSIA results demonstrated that small bulky and electropositive side chains at R3 position and hydrophobic groups at R7 and R8 positions will increase their activity, and intra-molecular hydrogen bonds between residues 1 and 4 are necessary to maintain the pharmacophoric conformation of RAs. These results may be helpful in designing novel and potential anti-tumor RAs.