Identification of potent and selective TACE inhibitors via the S1 pocket
ABSTRACT By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
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- "as PDB entries 1BKC , 1ZXC  and 2A8H  respectively. In addition PDB entry 2I47 , where the bound ligand contains a substituted isoxazole ring at the S 2 TACE sub-site, provides a suitable protein conformation for the docking of 2E. Finally, the protein conformation in 1ZXC also proved suitable for the docking of the sulfonamide 2B. "
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 bioavailability 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-α TACE has been a key target for pharmaceutical intervention in the treatment of rheumatoid arthritis. An extensive 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 extensive 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.Journal of molecular graphics & modelling 11/2010; 29(3):436-42. DOI:10.1016/j.jmgm.2010.08.006 · 2.02 Impact Factor
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ABSTRACT: A fundamental requirement for medium access control (MAC) protocols is to provide a unified bandwidth-on-demand platform to support an integrated mix of multimedia traffic with different QoS requirements, whilst stabilising contention-based access to achieve optimal throughput. Distributed queuing request update multiple access (DQRUMA) is an efficient bandwidth-on-demand fair-sharing protocol for wireless packet networks with multi-code CDMA. This paper therefore proposes a MAC protocol that maximises the channel throughput based on DQRUMA using a Bayesian feedback control model. Original contributions in the paper include: (1) an enhanced DQRUMA model by randomisation of packet transmissions, which is developed from single cell to cellular CDMA networks; and (2) a proposed control strategy which ensures that the system operates steadily at the optimal access throughput point. Numerical results and simulation verify the proposed protocolVehicular Technology Conference, 1998. VTC 98. 48th IEEE; 06/1998
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ABSTRACT: Structure-based methods were used to design beta-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based assays. These analogs exhibit excellent in vitro potency against isolated TACE enzyme and show good selectivity for TACE over the related metalloproteases MMP-2, -13, and -14.Bioorganic & Medicinal Chemistry Letters 09/2007; 17(15):4333-7. DOI:10.1016/j.bmcl.2007.05.022 · 2.33 Impact Factor