Fragment-based discovery of inhibitor scaffolds targeting the metallo-β-lactamases NDM-1 and VIM-2

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• 作者：Tony Christopeit ; Hanna-Kirsti S. Leiros ; ^{hanna-kirsti.leiros@uit.no" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FBDD ; fragment based drug discovery ; MBL ; metallo-β-lactamase ; PAINS ; Pan Assay Interference Compounds ; SBL ; serine-β-lactamases ; NDM ; New Delhi metallo-β-lactamase ; VIM ; Verona integron-encoded metallo-β-lactamase ; IMP ; Imipenemase ; SPR ; surface plasmon resonance ; ka ; on-rate ; kd ; off-rate ; KD ; dissociation constant ; QM ; quantum mechanics ; QPLD ; QM-polarized ligand docking
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：1973-1977
• 全文大小：1387 K

文摘

Metallo-β-lactamases (MBLs) render bacteria resistant to β-lactam antibiotics and are interesting drug targets to prevent the hydrolysis of β-lactam antibiotics. So far, there are no MBL inhibitors in clinical use and particularly the design of broad spectrum inhibitors targeting several MBLs has been difficult. In this study, we report four fragments inhibiting the clinically relevant New Delhi metallo-β-lactamase 1 (NDM-1) and Verona integron-encoded metallo-β-lactamase 2 (VIM-2). The fragments were identified from a library using an orthogonal screening strategy combining a surface plasmon resonance (SPR) based assay and an enzyme inhibition assay. The identified fragments showed dissociation constants (K_D) ranging from 181 to 2100 μM. The binding mode of the fragments was explored using QM-polarized ligand docking. All four fragments represent interesting scaffolds for the design of broad-spectrum MBL inhibitors.