Exploring the chiral space within the active site of α-thrombin with a constrained mimic of d-Phe-Pro-Arg — design, synthesis, inhibitory activity, and X-ray structure of an enzyme–inhibitor complex

✍ Scribed by Stephen Hanessian; Elise Balaux; Djorde Musil; Lise-Lotte Olsson; Ingemar Nilsson

• Publisher: Elsevier Science
• Year: 2000
• Tongue: English
• Weight: 356 KB
• Volume: 10
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/s0960-894x(99)00669-1

✦ Synopsis

An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar inhibition of alpha-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions.