Antitumor Study In Silico And Synthesis Of Honokiol Derivatives Based On Virtual Screening

Objective Cancer is a severe disease threatening the health and lives of human being. Current treatments of cancer have limited effectiveness and numerous serious unintended side effects. Following advances on the pathogenetic mechanisms of cancer, more and more regulatory protein and drug targets relating cancer have been clarified, promoting the development of anticancer drugs from cytotoxic drugs to targeted drugs. The Chinese medicine have afforded a rich source of anticancer agents with multi-targeted and low toxicity. Hence, our study focused on the active component isolated from Chinese traditional herb magnolia—honokiol with potential anticancer activities. To understand the antitumor mechanisms of honokiol at molecule level, we investigate the potential antitumor targets of honokiol with reverse docking approach. To increase the activity of honokiol, we designed and synthesized a serial of honokiol analogues based on the existing SAR study of honokiol and virtual screening method.Methods The reverse docking study was performed on the autodock4.2 program, honokiol was used as a probe,16 antitumor targets were selected as screen objects, binding energyΔG and inhibition constant Ki were used to evaluate the docking results. Based on the structures of matrix metalloproteinases 2/9, as well as the combination principle, two serials of honokiol derivatives were designed. Virtual screening method with autodock4.2 program was used to evaluate the activities of the designed analogues. All of the three dimensional structures of compounds prepared for docking study were constructed by the Corina program. Nine honokiol analogues were synthesized by Williamson reaction and alkylation reaction, the structures of which were confirmed by 1H NMR, MS.Results Reverse docking results revealed that the binding energy between honokiol and COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are ranked at the top of the list, in which the binding energy between honokiol and COX-2 is higher than the positive control compound—flurbiprofen. In addition, molecule modeling showed that honokiol inserted into the S1' pocket of MMP2/9, and leave space for structural modification. Virtual screening results showed that the series II of honokiol derivatives possessed higher affinity than the series I analogues, as well as space match, with MMP-9. Nine honokiol derivatives of series II have been synthesized, all of which have not been reported in literature.Conclusions COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are the potential binding targets of honokiol. The structure of N1-substituted benzyl-(5-halogeno) uracil at 4-position of hydroxyl group of honokiol plays important role in the affinity between honokiol derivatives of seriesⅡand MMP2/9.