S Ren1, S K Wu, E J Lien. 1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles 90033, USA. sren@hsc.usc.edu
Abstract
PURPOSE: 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.
PURPOSE: 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.
Authors: E A Kuo; P T Hambleton; D P Kay; P L Evans; S S Matharu; E Little; N McDowall; C B Jones; C J Hedgecock; C M Yea; A W Chan; P W Hairsine; I R Ager; W R Tully; R A Williamson; R Westwood Journal: J Med Chem Date: 1996-11-08 Impact factor: 7.446