3D-QSAR Studies of Isatin Derivatives with Anti-Cancer In Vitro: Advanced CoMFA, CoMSIA and Docking Methods

Abstract

Three-dimensional quantitative structure–activity relationship (3D-QSAR) and docking methods were performed to study 47 tubulin inhibitors, isatin derivatives with anticancer activity against human monocyte-like histiocytic lymphoma human U937 cells. The established 3D-QSAR model from Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Index Analysis (CoMSIA) approaches show a significant statistical quality and a satisfying predictive ability, with high correlation coefficient value (R2=0.936, R2=0.970) and cross-validation coefficient value (Q2=0.821, Q2=0.884) of CoMFA and CoMSIA, respectively. The predictive ability of the CoMFA (R2 test=0.607) and CoMSIA (R2 test=0.650) model was confirmed by a test set. The CoMFA, CoMSIA contour maps and docking analyses indicate that the substituent R1 should be oxygen which better than azotes to forms a more potent inhibitor against tubulin enzyme and R2, R3, R4 and R5 substituents should be higher electronegative but R6 should be a bulky aromatic group like a methylnaphthol monosubstituted or disubstitued by OCH3. The interaction information between target and ligand was presented such the useful theoretical references for analyzing to understand the action mechanism, designing new more potent inhibitors and optimizing their activities prior to synthesis.