In-silico evidence of ADAM metalloproteinase pathology in cancer signaling networks.

Lack of effective targeted therapies often contributes to poor clinical outcomes of aggressive malignancies associated with drug resistance, angiogenesis and metastasis. Literature mining portrays the major role of ADAM17 in cancer and inflammatory diseases. However, it is quite challenging to design a candidate drug for targeting ADAM17 due to its structural similarity with the catalytic domain of the matrix metalloproteases (MMPs). The present study reports the protein-protein interaction analysis of ADAM17, along with the molecular docking and MD simulation studies for the screened compounds. Our analysis confirms the association of ADAM17 with numerous oncogenes that facilitates cancer progression and inflammation, especially the members of the Notch, receptor tyrosine kinase (RTK) and TNFα pathways. The outcome provides evidence that the prevalent protease ADAM17 could attribute to cancer signaling regulation though the shedding of various inflammatory and oncogenic molecules. We have also exploited the analogues of the existing inhibitors, with an aim at discovering a potent molecule, which could be repurposed as a drug against ADAM17 inflicted cancer progression. Upon stringent screening, we delineated our choice into two specific compounds (I6 and I9; analogues of IK862, a type of y-lactam hydroxamates), possessing the lowest binding energy (-9.1 Kcal/mol), stable MD-simulation studies and superior pharmacodynamic properties. The current information illustrates the avenue to persuade further research on targeting ADAM17 with small molecular compounds (I6 and I9) in cancer therapeutics.Communicated by Ramaswamy H. Sarma.