Enzyme inhibition potency enhancement by active site metal chelating and hydrogen bonding induced conformation-restricted cyclopropanecarbonyl derivatives.
Two cyclopropanecarbonyl derivatives were independently found to be 15 and 14 times more potent than the corresponding isopropylcarbonyl analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase and dihydroorotate dehydrogenase, respectively. A thorough examination of the co-crystal structures of available enzyme inhibitor complexes and the conformation of X-ray crystal structures of several synthesized cyclopropanecarbonyl derivatives revealed that this enhancement by one order of magnitude of inhibition potency exhibited by cyclopropanecarbonyl derivatives in both enzymes is probably caused by respective metal chelating and hydrogen bonding interactions at the ligand-receptor binding site. These specific interactions subsequently cause the cyclopropyl group of the molecules to adopt a fixed bisected conformation, which is unavailable for isopropylcarbonyl derivatives.
Kuo
Pei-Yu
PY
Department of Chemistry, Tunghai University, 181, Taichung-Kang Rd. Sec. 3, Taichung, Taiwan 407, Taiwan.
Shie
Tien-Lan
TL
Chen
You-Sheng
YS
Lai
Jiun-Ting
JT
Yang
Ding-Yah
DY
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008670:Metals / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D003521:Cyclopropanes; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D008670:Metals; C015766:cyclopropanecarboxylic acid; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D015951:Factor Xa