Abstract
The active metabolite of the novel immunosuppressive agent leflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the biological activities of a series of analogues of the active metabolite. The statistical results, cross-validated rCV2 (0.664) and non cross-validated r2 (0.687), show a good predictive ability. The final SOMFA model provides a better understanding of DHODH inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme.
Highlights
The dihydroorotate dehydrogenase (DHODH) ia an essential mitochondrial enzyme that catalyzes the flavin mononucleotide-dependent formation of orotic acid, a key step in de novo pyrimidine biosynthesis [1,2]
The purpose of this paper is to describe the application of self-organizing molecular field analysis, Self-organizing molecular field analysis (SOMFA), on the analogues of the active metabolite of leflunomide, to analyze the three-dimensional quantitative structure-activity relationships (3D-Quantitative structure-activity relationship (QSAR)) and to determine the structural requirements of this series of analogues for optimum activity
SOMFA, a novel 3D-QSAR methodology, is employed for the analysis with the training set composed of 42 various compounds, from which biological activities are known
Summary
The dihydroorotate dehydrogenase (DHODH) ia an essential mitochondrial enzyme that catalyzes the flavin mononucleotide-dependent formation of orotic acid, a key step in de novo pyrimidine biosynthesis [1,2] This enzyme is an attractive chemotherapeutic target in various pathogens, such as Plasmodium falciparum and Helicobacter pylori, and for the treatment of human disease, such as cancer, malaria and rheumatoid arthritis [3,4,5]. The purpose of this paper is to describe the application of self-organizing molecular field analysis, SOMFA, on the analogues of the active metabolite of leflunomide, to analyze the three-dimensional quantitative structure-activity relationships (3D-QSAR) and to determine the structural requirements of this series of analogues for optimum activity. The 3D-QSAR together with the modeling studies will provide a more precise elucidation of the molecular forces involved in the
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