Department of Chemistry, St. Edward's University, 3001 South Congress Ave., Austin, TX 78704, USA.
J Mol Graph Model. 2010 Nov;29(3):436-42. doi: 10.1016/j.jmgm.2010.08.006. Epub 2010 Sep 21.
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.
基质金属蛋白酶家族一直是过去三十年大部分药物研发的靶点，但由于缺乏选择性、较差的口服生物利用度和体内效力降低等原因，其研发进展一直受到阻碍。表面表达的金属蛋白酶 ADAM10 和 ADAM17，后者也称为 TACE，在各种生理过程中发挥着重要作用，特别是在组织修复和发育方面。由于 TACE 在细胞因子 TNF-α 的释放中起作用，因此它一直是治疗类风湿关节炎药物干预的关键靶点。已经开发了大量基于磺酰胺骨架的 TACE 小分子抑制剂的结构活性数据，其中包含关键的炔基取代基。我们对该配体组的选定成员进行了广泛的分子建模研究，以更好地了解开发更有效 TACE 抑制剂所涉及的结构细微差别，并确定基于结构设计的那些元素可以提高此类抑制剂对 TACE 相对于 ADAM10 的选择性。结果包括鉴定一个灵活的环，类似于在其他 MMP 中发现的环，它在确定抑制剂效力方面起着微妙但重要的作用。
