DIHYDROOROTATE DEHYDROGENASE INHIBITORS - QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

Purpose. The main purpose of this study is to analyze the quantitative structure-activity relationship of two series of dihydroorotate dehyd rogenase inhibitors (leflunomide and quinoline carboxylic acid analogu es), 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 coef ficient and the molar refractivity values. The molecular modeling was performed using the HyperChem(R) program. Results. Statistically signi ficant correlations were obtained using a combination of 3-4 parameter s. The structural requirements for optimum activity and critical regio ns for the inhibitory activity of dihydroorotate dehydrogenase were id entified. Conclusions. The quantitative structure-activity relationshi p analysis demonstrated that two series of dihydroorotate dehydrogenas e 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 modifica tion and improvement of inhibitors of this important enzyme.