In Silico Evaluation of Some Dihydroxamic Derivatives of Diphenylether, as Hybrid Hydroxamic-Allosteric Inhibitors for MMP13

摘要

Synthetic inhibitors for MMPs may become ef fective if they include a functional group as hydroxamic acid, carboxylic acid, sulfhydryl, etc. capable of binding the catalytic Zn, while at least one functional group provides a hydrogen bond interaction with the enzyme backbone, and one or more side chains will undergo effective van der Waals interactions with the enzyme subsites. Due to the fact that previous clinical trials that have used small inhibitor molecules and especially hydroxamic derivatives (batiamastat, marimastat) have shown poor clinical results and even malignancy rebound, the next generation of MMP inhibi tors is directed toward exodomain-substrate interactions. In the present study we have docked both known and ex perimentally tested inhibitors and also new proposed inhibitor models. Then we have compared binding affinities of the known compounds with those of three newly proposed ligands. The purpose of this study was evaluate the affinity degree of these hypothetic hybrid inhibitors for the catalytic domain of MMP13. The docking study performed with the open source software Autodock Vina, have generated promising results regarding the possibility to propose hypothetical but potent hybrid hy droxamic-allosteric inhibitors for the catalytic domain of MMP. Interactions between the newly proposed ligands and the catalytic site of MMP13 show new interesting alternative options for tunnel-like catalytic site enzymes. It appears that the direct Zn ion coordination is not solely responsible for enzyme inhibition but also allosteric inhibition may play an important role. Our results show that the proposed inhibitors, nominated as ligands 3, 4 and 5, mainly dihydroxamic derivatives of di phenylether, has both hydroxamic potency but als the ability to perform allosteric inhibition at least for MMP13 catalytic site. Further studies will consider evaluation of these theoretical inhibitors by docking on other MMPs with different S1' pock ets.Regarding the proposed extended docking studies, we sup pose that the synthesis of ligand-5 and the experimental data should confirm our molecular docking results.