STUDIES ON THE STRUCTURE-ACTIVITY RELATIONSHIP OF RETINOIDS: 3D-QSAR OF RETINOIDAL ANTI-CARINOGENIC ACTIVITIES

Using comparative molecular field analysis(CoMFA),a 3D-QSAR model of anti-carcinogenicity for a series of retinoids was estamshed.The CoMFA model was validated and built bycross-validation(leave-one-out) and non-cross-validation(randomizing)techniques. The significantPLS cross-validated value R²_CV(0.905)indicated that the model could be used as a predictive tool forfurther design of retinoids with high activity.The activities of three compounds excluded from thecorrelation analysis were computed using this model,small residues being obtained.Based on the conformers with the lowest energy,no statistical significance existed(R²_CV=0.405).A performance of minor rotation around a single bond for partial compounds provided the conformerswith the variation in energy limit less than 2 kcal·mol^-1,by which a correlation analysis was run witha satisfactory relationship between the perturbed confonners and the activities,this suggested thelowest energy cOnformers to be unlikely the pharmacophoric conformers.Superimposition of ligand fields was carried out to mimic the environment of ligands interactingwith their receptor, and to visualize the steric and electrostatic behaviors of groups and/or atomsbetween ligands and receptor.The molecular field model as a template is able to predict activities and,to some extent,to map the topological and physico-chemical characteristics of receptor.