4 research outputs found
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
We describe the use
of comparative structural analysis and structure-guided
molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase
13 (MMP-13). We applied a three-step process, starting with a comparative
analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known
MMP-13路inhibitor complexes followed by molecular design and synthesis
of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores
of the chelating inhibitors (<i>S</i>)-<b>10a</b>,
(<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding
within the MMP-13 active site, the Zn<sup>2+</sup> chelating unit
was replaced with nonchelating polar residues that bridged over the
Zn<sup>2+</sup> binding site and reached into a solvent accessible
area. After two rounds of structural optimization, these design approaches
led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding
site of MMP-13 and surround the catalytically active Zn<sup>2+</sup> ion without chelating to the metal. These compounds exhibit at least
500-fold selectivity versus other MMPs
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
We describe the use
of comparative structural analysis and structure-guided
molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase
13 (MMP-13). We applied a three-step process, starting with a comparative
analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known
MMP-13路inhibitor complexes followed by molecular design and synthesis
of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores
of the chelating inhibitors (<i>S</i>)-<b>10a</b>,
(<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding
within the MMP-13 active site, the Zn<sup>2+</sup> chelating unit
was replaced with nonchelating polar residues that bridged over the
Zn<sup>2+</sup> binding site and reached into a solvent accessible
area. After two rounds of structural optimization, these design approaches
led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding
site of MMP-13 and surround the catalytically active Zn<sup>2+</sup> ion without chelating to the metal. These compounds exhibit at least
500-fold selectivity versus other MMPs
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
We describe the use
of comparative structural analysis and structure-guided
molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase
13 (MMP-13). We applied a three-step process, starting with a comparative
analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known
MMP-13路inhibitor complexes followed by molecular design and synthesis
of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores
of the chelating inhibitors (<i>S</i>)-<b>10a</b>,
(<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding
within the MMP-13 active site, the Zn<sup>2+</sup> chelating unit
was replaced with nonchelating polar residues that bridged over the
Zn<sup>2+</sup> binding site and reached into a solvent accessible
area. After two rounds of structural optimization, these design approaches
led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding
site of MMP-13 and surround the catalytically active Zn<sup>2+</sup> ion without chelating to the metal. These compounds exhibit at least
500-fold selectivity versus other MMPs
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors
We describe the use
of comparative structural analysis and structure-guided
molecular design to develop potent and selective inhibitors (<b>10d</b> and (<i>S</i>)-<b>17b</b>) of matrix metalloproteinase
13 (MMP-13). We applied a three-step process, starting with a comparative
analysis of the X-ray crystallographic structure of compound <b>5</b> in complex with MMP-13 with published structures of known
MMP-13路inhibitor complexes followed by molecular design and synthesis
of potent but nonselective zinc-chelating MMP inhibitors (e.g., <b>10a</b> and <b>10b</b>). After demonstrating that the pharmacophores
of the chelating inhibitors (<i>S</i>)-<b>10a</b>,
(<i>R</i>)-<b>10a</b>, and <b>10b</b> were binding
within the MMP-13 active site, the Zn<sup>2+</sup> chelating unit
was replaced with nonchelating polar residues that bridged over the
Zn<sup>2+</sup> binding site and reached into a solvent accessible
area. After two rounds of structural optimization, these design approaches
led to small molecule MMP-13 inhibitors <b>10d</b> and (<i>S</i>)-<b>17b</b>, which bind within the substrate-binding
site of MMP-13 and surround the catalytically active Zn<sup>2+</sup> ion without chelating to the metal. These compounds exhibit at least
500-fold selectivity versus other MMPs