In-silico evidence of ADAM Metalloproteinase Pathology in Cancer Signalling Networks

Purpose: Literature mining portrays major role of ADAM17 in cancer and inflammation, but due to its structural similarity of the catalytic site to that of the MMPs, it is a challenging task to design a candidate drug for targeting ADAM17. Herein, we have exploited the analogues of some existing inhibitors, with an aim at discovering a potent inhibitor, which might be repurposed as a drug against ADAM17 inflicted cancer progression. Methods: STRINGS database provided us with the ADAM17 mediated protein-protein interaction network. Gene ontology analysis was performed using WebGestalt to obtain the interacting proteins in biological processes, along with their role in signalling pathway and the gene-disease associations. The analogues were screened using the PubChem database. Molecular docking and MD-simulation studies were performed to obtain the dynamic properties of the protein-inhibitor complex. Furthermore, the pharmacodynamic properties of the compounds ascertained their inhibitory and drug-likeliness properties. Results: Our analysis provided sufficient evidence in considering ADAM17 as an eminent regulator of various cancer signalling pathways, which can be considered as a predominant marker in cancer patients. Upon screening of the existing analogues, we delineated our choice into two specific compounds (I6 and I9, analogues of IK862), possessing the lowest binding energy (-9.1 Kcal/mol), stable MD-simulation studies and superior pharmacodynamic properties. Conclusion: The present information paves the avenue to persuade further in-vitro and in-vivo research to provide the efficacy of inhibiting ADAM17 with small molecular compounds (I6 and I9) in the treatment of various malignancies.