Screening Based On Computer Aided Drug Design And Cell Viability Evaluation Of Retinoids, Flavonoid And Stilbene Derivatives

Computer-aided drug design (CADD) is a multi-disciplinary cross-cutting area, and it can simulate and calculate the relationship between ligands and receptors based on computer science. The techniques of CADD include pharmacophore model, molecular docking, homology modeling, potential drug targets identification via large-scale reverse pharmacophore mapping and so on.Retinoic acid receptor alpha (RARα) has been considered as one of the most important targets for the treatment of acute promyelocytic leukemia (APL). First, ligand-based pharmacophore modeling of a series of structurally diverse RARαagonists were applied to acquire the binding model (KI pharmacophore model) and the efficacy model (EC50pharmacophore model) of RARα.In this paper, a three dimensional quantitative structure-activity relationship (3D-QSAR) in Discovery Studio2.5was used to generate pharmacophore models. Via Fischer’s randomization validation and Maximum Unbiased Validation (MUV), the best pharmacophore model for KI pharmacophore model was Hypo IK and for EC50pharmacophore model was Hypo7E. Virtual screening of National Cancer Institute (NCI) database using Hypo1K and Hypo7E was performed respectively. Six potent compounds in the retrieved hits with a CAS number were confirmed to be effective on leukemia cell lines and other tumor in the literatures. As evident from the validation and the biological screening results, it can be concluded that the Hypo1K and Hypo7E were reliable and useful tools for lead optimization of novel RARa agonists.Second, flavonoid derivates synthesized by our research group were tested for their biological activity against human hepatoma cell line HepG2and human normal hepatic cell line L-O2.Compound9,29and37exhibited strong inhibitory activity on HepG2cell line with IC50values of9.0μmol/L,5.5μmol/L and6.6μmol/L. Compound23showed the best inhibition on L-O2cell line with IC50values of8.2μmol/L. PharmMapper server was used to find the potential target of flavonoid derivatives. Thymidylate synthase was the potential target and was verified by molecular docking.Finally, stilbene derivates synthesized by our research group were tested for their biological activity against HepG2and L-O2cell lines. When double methoxy substituted at the phenyl ring of the styryl moiety, compound (S001, IC50=26.3μmol/L; S005, IC50=48.2 μmol/L and S007, IC50=52.2μmol/L) with N-methyl substitution at the benzimidazole scaffold showed lower inhibitory activity than the compound (S002, IC50=77.6μmol/L; S006, IC50=80.6μmol/L and S008, IC50=65.2μmol/L) without methyl at the benzimidazole scaffold. In order to further investigate the underlying mechanism of the result, we docked stilbene compounds into soiuble epoxide hydrolaseand the interaction between the compounds and receptor verified this pattern.