Journal of Molecular Graphics and Modelling 29 (2010) 436–442 Contents lists available at ScienceDirect Journal of Molecular Graphics and Modelling journal homepage: www.elsevier.com/locate/JMGM Acetylenic inhibitors of ADAM10 and ADAM17: In silico analysis of potency and selectivity Eamonn F. Healy ∗ , Pablo Romano, Moises Mejia, Gunnar Lindfors III Department of Chemistry, St. Edward’s University, 3001 South Congress Ave., Austin, TX 78704, USA article info Article history: Received 26 June 2010 Received in revised form 18 August 2010 Accepted 21 August 2010 Available online 21 September 2010 Keywords: ADAM17 TACE ADAM10 Metalloproteinase inhibition docking Molecular modeling hydroxamate abstract The matrix metalloproteinase family has been a pharmaceutical target for most of the last three decades, but success has been hampered by unwanted side effects caused by lack of selectivity, poor oral bioavail- ability and decreased potency in vivo. The surface-expressed metalloproteinases ADAM10 and ADAM17, the latter also referred to as TACE, play important roles in various physiological processes, especially involving tissue repair and development. Because of its role in the release of the cytokine TNF- TACE has been a key target for pharmaceutical intervention in the treatment of rheumatoid arthritis. An exten- sive body of structural activity data has been developed for a series of small molecule inhibitors of TACE based on a sulfonamide scaffold containing key acetylenic substituents. We have undertaken an exten- sive molecular modeling study of select members of this ligand group to better understand the structural nuances involved in the development of ever more potent TACE inhibitors, and identify those elements of structure-based design that would enhance the selectivity of such inhibitors for TACE over ADAM10. Results include the identification of a flexible loop, comparable to that found in other MMPs that plays a subtle, yet significant, role in determining inhibitor potency. © 2010 Elsevier Inc. All rights reserved. 1. Introduction The matrix metalloproteinases (MMPs) and the ADAMs (A Disintegrin And Metalloproteinase domains) are zinc containing proteolytic enzyme families implicated in a variety of physiolog- ical processes such as inflammation, wound healing and tissue development. The pathologies associated with either increased or decreased activities of these enzymes include, but are not limited to, conditions such as rheumatoid arthritis, diabetes, osteopenia, Alzheimer’s disease and cancer. The roles of metalloproteinases in cancer are complicated by the fact that most tumor cells, and frequently the surrounding stromal cells, synthesize MMPs to facilitate invasion into surrounding connective tissue and promote metastasis. The structural similarity between the active sites of various MMPs and ADAMs has presented a major challenge for the design of specific inhibitors. In addition to the unwanted side effects caused by lack of selectivity, other reasons for the low success rate in the development of therapeutic targets to date include poor oral bioavailability and decreased potency in vivo. Most of the structure- based inhibitor design thus far has focused on ligands containing a zinc-binding group (ZBG) and substituents designed to occupy the S 1 ′ –S 3 ′ enzyme sub-sites as shown in Fig. 1A. Whereas the ∗ Corresponding author. Tel.: +1 512 448 8467; fax: +1 512 448 8492. E-mail address: healy@stedwards.edu (E.F. Healy). zinc-binding group provides high affinity but low specificity, P 1 ′ substituents are major determinants of both potency and selectiv- ity. For most MMPs and ADAMs a wide range of P 2 ′ substituents are tolerated, including rings that cyclize to P 3 ′ , and steric bulk at this position is often beneficial for oral bioavailability. A wide range of P 3 ′ substituents are also well tolerated, and polar or charged groups at this position can affect biliary excretion. Also called TACE, or Tumor Necrosis Factor (TNF-) convert- ing enzyme, ADAM17 is implicated in Rheumatoid Arthritis (RA) through the production of the pro-inflammatory cytokine TNF-. A number of crystal structures are available from the Research Col- laboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) for the catalytic domain of TACE co-crystallized with vari- ous ligands. As shown in Fig. 1A the binding of the peptidomimetic TAPI-2, Fig. 2A, to TACE clearly demonstrates the effectiveness of the hydroxamate ZBG. The isobutyl P 1 ′ substituent binds in the largely hydrophobic S 1 ′ pocket, while the bulky tert-butyl P 2 ′ sub- stituent sits in the shallow S 2 ′ sub-site. The methyl P 3 ′ substituent points towards the large S 3 ′ cleft with the diaminoethyl group extending out from the active site. Beyond their limited selectivity inhibitors such as TAPI-2 suffer from other deficiencies common to peptidomimetics, such as poor solubility, metabolic lability and rapid clearance. In the pursuit of selective non-peptide TACE inhibitors much work has been done on the structure-based design of sulfonamide hydroxamates. The original series of sulfonamide hydroxamate inhibitors were based on an anthanilic acid scaffold [1], with the 1093-3263/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2010.08.006