Studies on structure-activity relationship of phenothiazines (PTZs) forinhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) has been made invitro. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows:2-COC_3 H_7 > 2-CF_3 > 2-COCH_3 > H. The type of piperazinyl substitution also significantlyaffected potency against MDR. The results show the order: CH_3 > COOC_2 H_5 > C_2 H_4 OH. Inaddition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZwas tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR andPKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried toexplore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinityPKC-modulator. The infor-mation may be used in the rational design of more effective drugs.
Using comparative molecular field analysis (CoMFA), a 3D-QSAR model of anticarcinogenicity (inhibiting the induction of ODC) for a series of retinoids was established. The CoMFA model was validated and built by cross-validation (leave-one-out) and non-validation (randomizing) techniques. The significant PLS cross-validated value R2CV (0.905) indicated that the model could be used as a predictive tool for further design of new molecules with high activity. The activities of three compounds excluded from the correlation analysis were computed using this model, small residues obtained. Based on the conformers with the lowest energy, no statistical significance existed (R2CV = 0.405). A performance of minor rotation around a single bond for several compounds provided the conformers with the variation in energy limit less than 2 kcal / mol, by which a correlation analysis was run with a satisfactory relationship between the perturbed conformers and the activities, suggesting that the lowest energy conformers for some compounds be unlikely the pharmacophoric conformers. Superimposition of ligand fields was carried out to mimic the environment of ligands interacting with their receptor, and to visualize the steric and electrostatic behaviors of groups and / or atoms between 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.
Fast and precise prediction of the receptor-ligand binding constant is an important aspect of structure-based drug design. Almost all de novo design methods or 3D database search methods tend to structure generation instead of structure evaluation. In this article, epididymal retinoic acid binding protein (ERABP) was used as a template to simulate the interaction between retinoids and their receptor. We deduced an equation predicting the drug-receptor binding constant. Furthermore, the conformers after docking were used in CoMFA analysis to get a pharmacophore model of this series of compounds.
