Novel Prostaglandin D Synthase Inhibitors Generated by Fragment-Based Drug Design

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• 作者：Morten Hohwy ; Loredana Spadola ; Britta Lundquist ; Paul Hawtin ; Jan Dahmé ; n ; Ib Groth-Clausen ; Ewa Nilsson ; Sofia Persdotter ; Karin von Wachenfeldt ; Rutger H. A. Folmer ; Karl Edman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2178 - 2186
• 全文大小：1696K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein–ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC₅₀ below 1 µM in the in vitro assay. The best inhibitor (IC₅₀ = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway.