3D-QSAR studies on a series of dihydroorotate dehydrogenase inhibitors: analogues of the active metabolite of leflunomide

• Published in: International journal of molecular sciences Vol. 12; no. 5; pp. 2982 - 2993
• Main Authors: Li, Shun-Lai, He, Mao-Yu, Du, Hong-Guang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.05.2011; Molecular Diversity Preservation International (MDPI)
• Subjects: 3D-QSAR; Biosynthesis; Dehydrogenases; DHODH inhibitors; Dihydroorotate Dehydrogenase; DMARDs design; Enzyme Inhibitors - chemistry; Enzymes; Immunosuppressive agents; Immunosuppressive Agents - chemistry; Isoxazoles - chemistry; Leflunomide; Models, Molecular; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Quantitative Structure-Activity Relationship; Rheumatoid arthritis; SOMFA; Beijing China; China; 3D-QSAR; SOMFA; DHODH inhibitors; DMARDs design
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms12052982

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 r(CV) (2) (0.664) and non cross-validated r(2) (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.