Design Of Novel CombretastatinA-4 As Antitumor Based On 3D-QSAR Molecular Docking And Molecular Dynamics Simulations

Combretastatin A-4, a inhibitor of tubulin, have good activity against microtubule polymerization and mitotic and also have competitive inhibition for colchicine promots microtubule polymerization. And it is also a anticancer drug is developing for destruction pipe systems firstly. In order to improve CA-4 activity and reduce toxicity, A-ring, B ring and bridge bond were modified to obtain a series of CA-4 analogues. In this paper, the structure-activity relationships of 81 CA-4 analogues are studied by 3D-QSAR. The samples were randomly divided into a training set of 69 compounds and a test set of 12 compounds, respectively. The 3D-QSAR models show significant statistical quality and satisfactory predictive ability. The correlation coefficient (R2) and cross-validation coefficient (q2) of CoMFA are 0.976 and 0.659; the R2 and q2 of CoMSIA are 0.937 and 0.637, respectively. Moreover, it is very interesting to find that the predictive values of the 3D-QSAR models are in good agreement with the experimental values of our synthetic CA-4 analogues. Based on the built models, several new inhibitors were designed. In this paper, we study the relationship of CA-4 analogues structure and activity data and interactions between inhibitors and tubulin by a combination of molecular modeling techniques including 3D-QSAR, molecular docking and molecular dynamics (MD) in order to obtain important structural effects inhibitor activity and guide to design CA-4 analogs. And we can obtain the optimized structural and activity prediction. Moreover, we can design and synthesis of more effective targeted molecular drugs to treat cancer.The results show that:1、The built 3D-QSAR models are reliable and have high predictive ability.2、Based on the built models, several new good inhibitors were designed and all designed compounds are more potent compared with CA-4. Moreover, the 35d is a potentially high active inhibitor3、The docking results showed that Tyr202 Val238, Asp251, Asn258, Lys352, Ala354, Cys241, Thr317, Ile318, Gln247, Thr353, Ala250, Leu242, Leu252, Lys254, Leu255, Met259 and Ala316 are important amino acid residues at colchicine binding sites. And the Gln247 residue plays an important role to form hydrogen bonds.4、The molecular dynamics results verified the reliability of the docking. Statistics of the binding energy calculated showed that the contribution of vander Waals force to the binding energy is the largest5、The results of 3D-QSAR contour maps and molecular dynamics showed introduction of F atom into the double bond of the cis-stilbene moiety in CA-4 analogues can obviously improve the inhibitory activity. Hence, when designing new compounds, we should keep the site of the F atom.