A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor-α Converting Enzyme:  Implications for Selectivity

Abstract

MMPs and TACE (ADAM-17) assume independent, parallel or opposite pathological roles in cancer, arthritis, and several other diseases. For therapeutic purposes, selective inhibition of individual MMPs and TACE is required in most cases due to distinct roles in diseases and the need to preserve activities in normal states. Toward this goal, we compared force-field interaction energies of five ubiquitous inhibitor atoms with flexible binding sites of 24 known human MMPs and TACE. The results indicate that MMPs 1−3, 10, 11, 13, 16, and 17 have at least one subsite very similar to TACE. S3 subsite is the best target for development of specific TACE inhibitors. Specific binding to TACE compared to most MMPs is promoted by placing a negatively charged ligand part at the bottom of S2 subsite, at the entrance of S1' subsite, or the part of S3' subsite that is close to catalytic zinc. Numerous other clues, consistent with available experimental data, are provided for design of selective inhibitors.

Acetylenic inhibitors of ADAM10 and ADAM17: In silico analysis of potency and selectivity

“…Of greater interest to us here is the binding pocket distal to S 1 , a cleft presumably representing the S 2 sub-site. Whereas a previous characterization identified this S 2 pocket as comprising residues His 409 to His 415 inclusive [28], inspection of Fig. 6A identifies the cleft as mainly defined by His 409 , Glu 414 and His 415 , with some definition also added by Val 353 .…”

Inhibitors of TACE and Caspase-1 As Anti-inflammatory Drugs

“…Due to active site similarity between TACE and the matrix metalloproteases (24 MMPs are currently known) [16,53], most TACE inhibitors described above inhibit one or more MMPs and have different selectivity profiles (see Table 1). Although the matrix metalloproteases are principally involved in remodelling of connective tissue, the precise role of each one in normal and disease states is not known in fine enough detail.…”

“…Even though the enzyme shares only a low sequence identity (12-15%) to the matrix metalloproteases (MMP), the active site of both TACE and the 24 currently known MMP's is structurally similar [16]. Two early studies showed that hydroxamatebased broad spectrum MMP inhibitors 1 and 2 could also reduce the production of TNF-α by inhibiting TACE [17,18].…”

Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

“…Therefore, of the many possible strategies to regulate TNF-a production, TACE inhibition has long been viewed as one of the most promising molecular targets (Newton et al, 2001). TACE shares many active site similarities with many other matrix metalloproteinases (MMPs) and ADAMs (Lukacova et al, 2005;Maskos et al, 1998). As a result, many of the early TACE inhibitors suffered from a lack of selectivity (Renkiewicz et al, 2003).…”