Modeling the anticarcinogenic action of retinoids by making use of the OASIS method. 3. Inhibition of the induction of ornithine decarboxylase by arotinoids.
A series of 15 congeneric aromatic retinoids (arotinoids) was subjected to a study of the conformational dependence of basic molecular descriptors, and the anticarcinogenic potency of the compounds was modeled by the sophisticated OASIS (optimized approach based on structural indices set) method. A high correlation was obtained for both two-variable models and three-variable models. The best models of these two kinds had correlation coefficients of 0.956 vs 0.988 and standard deviations s2 = 0.14 vs 0.04, respectively. The most significant variables were several interatomic and topological distances, which specify the optimum geometric drug-receptor fit. The group of significant electronic descriptors included characteristic pi-bond orders, the electronic charge at one atomic position in the tetrahydronaphthalene ring, the total electronic energy, and two electronic-topological indices. An electrostatic drug-receptor interaction was conjectured on this basis. A contribution of the through-cell membrane transport was inferred from the importance of molecular refraction in the best three-variable model. The models derived were validated by the leave-one-out procedure and by reproducing the activities of five arotinoids not included in the correlation sample.
Bonchev
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University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Seitz
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Mountain
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Balaban
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AT
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D065108:Ornithine Decarboxylase Inhibitors; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D016588:Anticarcinogenic Agents; D065108:Ornithine Decarboxylase Inhibitors; D012176:Retinoids; D009955:Ornithine Decarboxylase