Computer Modelling Studies Of Quinazolinone Derivatives As Novel MMP-13 Inhibitors And Synthesis Studies Of Dabigatran Derivatives

The matrix metalloproteinase-13?MMP-13?is the most efficient collagenase in the cleavage of type II collagen and is highly expressed in osteoarthritis?OA?cartilage.MMP-13inhibitors can block the degradation of OA cartilage in the body,and they are the most promising medicines for the OA treatment.Dabigatran etexilate,as a direct thrombin inhibitor,is the first new oral anticoagulant drug on the market in 50 years after warfarin.It has milestone significance.However,it still has some defects in the clinic,such as high-dose bleeding risk and low bioavailability.Therefore,it is important and meaningful to design and synthesize novel dabigatran derivatives for screening anticoagulant activity.In the first section,molecular modeling method of 53 quinazolinone derivatives as MMP-13 inhibitors were studied,including 3D-quantitative structure-activity relationship?3D-QSAR?,molecular docking and molecular dynamics?MD?simulation.The 3D-QSAR models with high reliability and predictability were constructed.Contour maps indicated that the bioactivity of MMP-13 inhibitor was mainly affected by electrostatic,hydrophobic and H-bond acceptor fields.Several key residues?Ala238,Thr245,Thr247,Met253,Asn215 and Lys140?were identified as important factors to improve the activity and stability of the inhibitor through hydrogen bonding and electrostatic interaction.Finally,8 novel MMP-13inhibitor candidates?D1-D8?with higher predictive activity were designed.50 ns MD simulations on the highest predicted activity compounds D3 and D8 revealed that the hydrogen bonding interaction with residues?Ser250 and Gly248?was enhanced,the small group in R2 and U-shaped conformation were beneficial to the improvement of activity.The results of this study provide theoretical basis and practical value for further structural optimization,design and synthesis of novel MMP-13 inhibitors.In the second section,according to the previous work by our research group,five new dabigatran derivatives?12a-12e?were designed,synthesized and characterized by ¹H NMR,¹³C NMR and HR-MS.In vitro anticoagulant activity of compounds 12a-12e and six compounds?12f-12k?previously synthesized showed that except for compound 12i,the other10 compounds exhibit comparable activity to the reference dabigatran and can be further studied as anticoagulant candidate compounds.Molecular docking and MD simulations?10 ns?were performed on three compounds?12a,12c and 12g?with high activity,which showed strong hydrogen bond and pi–pi stacking interactions with key residues Gly219,Asp189 and Trp60D play a key role in improving activity.The above results lay the foundation for the discovery of new anticoagulant candidates.