Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3 and Et Using Matrix Metalloproteinases As Structural Probes
Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harnes...
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| Published in | Journal of medicinal chemistry Vol. 63; no. 11; pp. 6225 - 6237 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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Amer Chemical Soc
11.06.2020
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| Abstract | Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor. |
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| AbstractList | Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor. |
| Author | Hoeppner, Sandra Daniliuc, Constantin G. Thiehoff, Christian Erdeljac, Nathalie Faust, Andreas Jumde, Ravindra P. Hirsch, Anna K. H. Gilmour, Ryan |
| Author_xml | – sequence: 1 givenname: Nathalie surname: Erdeljac fullname: Erdeljac, Nathalie organization: Westfalische Wilhelms Univ Munster, Organ Chem Inst, D-48149 Munster, Germany – sequence: 2 givenname: Christian surname: Thiehoff fullname: Thiehoff, Christian organization: Westfalische Wilhelms Univ Munster, Organ Chem Inst, D-48149 Munster, Germany – sequence: 3 givenname: Ravindra P. orcidid: 0000-0002-2674-9605 surname: Jumde fullname: Jumde, Ravindra P. organization: Helmholtz Ctr Infect Res HZI, Dept Drug Design & Optimizat, Helmholtz Inst Pharmaceut Res Saarland HIPS, D-66123 Saarbrucken, Germany – sequence: 4 givenname: Constantin G. orcidid: 0000-0002-6709-3673 surname: Daniliuc fullname: Daniliuc, Constantin G. organization: Westfalische Wilhelms Univ Munster, Organ Chem Inst, D-48149 Munster, Germany – sequence: 5 givenname: Sandra surname: Hoeppner fullname: Hoeppner, Sandra organization: Westfalische Wilhelms Univ Munster, European Inst Mol Imaging, D-48149 Munster, Germany – sequence: 6 givenname: Andreas surname: Faust fullname: Faust, Andreas organization: Westfalische Wilhelms Univ Munster, European Inst Mol Imaging, D-48149 Munster, Germany – sequence: 7 givenname: Anna K. H. orcidid: 0000-0001-8734-4663 surname: Hirsch fullname: Hirsch, Anna K. H. email: anna.hirsch@helmholtz-hips.de organization: Helmholtz Ctr Infect Res HZI, Dept Drug Design & Optimizat, Helmholtz Inst Pharmaceut Res Saarland HIPS, D-66123 Saarbrucken, Germany – sequence: 8 givenname: Ryan orcidid: 0000-0002-3153-6065 surname: Gilmour fullname: Gilmour, Ryan email: ryan.gilmour@uni-muenster.de organization: Westfalische Wilhelms Univ Munster, Organ Chem Inst, D-48149 Munster, Germany |
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| Title | Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3 and Et Using Matrix Metalloproteinases As Structural Probes |
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