Dihydroorotate dehydrogenase inhibitors: quantitative structure-activity relationship analysis.
OBJECTIVE
The main purpose of this study is to analyze the quantitative structure-activity relationship of two series of dihydroorotate dehydrogenase inhibitors (leflunomide and quinoline carboxylic acid analogues), and to determine the structural requirements for optimum activity of these analogues.


METHODS
A new CQSAR program was used in deriving regression equations and calculating the octanol/water partition coefficient and the molar refractivity values. The molecular modeling was performed using the HyperChem program.


RESULTS
Statistically significant correlations were obtained using a combination of 3-4 parameters. The structural requirements for optimum activity and critical regions for the inhibitory activity of dihydroorotate dehydrogenase were identified.


CONCLUSIONS
The quantitative structure-activity relationship analysis demonstrated that two series of dihydroorotate dehydrogenase inhibitors may bind to different binding sites on the enzyme. These results provide a better understanding of dihydroorotate dehydrogenase inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme.
Ren
S
S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles 90033, USA. sren@hsc.usc.edu
Wu
S K
SK
Lien
E J
EJ
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors