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A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual,SPR and NMR screening |
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| Institution: | 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China;3. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;1. School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China;2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China;3. Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China;1. School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China;2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China;3. Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China |
| Abstract: | NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of 15N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae. |
| Keywords: | NDM-1 Metal-binding pharmacophore Fragment-based drug design SPR NMR NDM-1"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"New Delhi Metallo-1 SPR"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"surface plasmon resonance NMR"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"nuclear magnetic resonance MBP"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"metal-binding pharmacophore MBL"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"metallo-"} {"#name":"italic" "_":"β"} {"#name":"__text__" "_":"-lactamase FBDD"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"fragment-based drug discovery PDB"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"Protein Data Bank CNCL PKU"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "_":"Chinese National Compound Library of Peking University LE"} {"#name":"keyword" "$":{"id":"k0115"} "$$":[{"#name":"text" "_":"ligand efficiency Hepes"} {"#name":"keyword" "$":{"id":"k0125"} "$$":[{"#name":"text" "_":"2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethansulfonic acid RU"} {"#name":"keyword" "$":{"id":"k0135"} "$$":[{"#name":"text" "_":"response unit DMSO"} {"#name":"keyword" "$":{"id":"k0145"} "$$":[{"#name":"text" "_":"dimethyl sulfoxide |
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