Virtual Screening And Molecular Dynamics Study Of Natural Flavonoid MMP-2/MMP-9 Inhibitors

Malignant tumors have become a serious threat to human life,health and social development.Therefore,finding and developing low-toxic,high-efficiency small molecule inhibitors has become an important topic for the treatment of malignant tumors.Matrix metalloproteinase-2（MMP-2）and matrix metalloproteinase-9（MMP-9）are closely related to malignant tumors,and are currently important targets for the development of anti-tumor drugs.However,the drugs currently used clinically have poor selectivity,high side effects,and low druggability.We plan to use MMP-2 and MMP-9 as research targets and use molecular simulation technology to screen natural flavonoids in order to obtain low-toxicity and high-efficiency anti-tumor inhibitors and provide a theoretical basis for drug research.The main research work is as follows:（1）Performance evaluation of docking software:The three docking software SYBYL Surflex-Dock,AutoDock Vina and AutoDock are used to evaluate the binding ability of MMP-2 and MMP-9 to the original ligand.The results show that the scoring function is high,to shows that the ligand molecule binds well to the target;Visual analysis shows that they can all form hydrogen bonds with key residues,and the KISS score value is higher than 0.7,indicating a higher degree of hydrogen bond reduction.SYBYL Surflex-Dock performs best in terms of docking stability,and AutoDock Vina software is superior to AutoDock software in terms of docking conformation.Based on the above factors,SYBYL Surflex-Dock and AutoDock Vina software were selected for virtual screening of MMPs.（2）Screening of potential natural flavonoid inhibitors of MMP-2:From the perspective of drug-like properties,2687 flavonoids were screened.Through three rounds of molecular docking and ADMET prediction,12 candidate compounds were obtained,and five of them were selected for visual analysis.It was found that they all have hydrogen bonding with the key residue Leu84,and they are all located in the S1’pocket of the key site.In addition,Gromacs molecular dynamics simulation studies have shown that Quercetagetin has a strong interaction with MMP-2,which is better than the initial docking conformation.（3）Screening of potential natural flavonoid inhibitors of MMP-9:Use SYBYL Surflex-Dock and AutoDock Vina software to screen natural flavonoids.Through three rounds of molecular docking and ADMET prediction,10 candidate compounds were obtained,and five of them were selected for visual analysis,It was found that they have hydrogen bonds with key residues Gly186,Leu188,His401,Tyr423 and Arg424.Gromacs molecular dynamics simulation studies have shown that Isosilybin A,Silybin-B and the key active amino acids of MMP-9 all play a role,and go deep into the S1’hydrophobic pocket.Among them,Silybin B also has a chelating effect with Zn²⁺.In summary,the use of molecular docking and molecular dynamics simulation technology has successfully screened MMP-2 and MMP-9 inhibitors from natural flavonoids,which provides research for the development of new drugs based on MMP-2 and MMP-9 targets.The basis also lays a theoretical foundation for the development and utilization of natural flavonoids.