Metergoline

Selective serotonin reuptake inhibitors (SSRIs) are known to have anticancer activity against different types of cancer. In this study, an integrative informatics approach was applied to identify compound and genetic perturbations that produce similar effects to SSRIs to formulate systems biology hypotheses and identify biological pathways involved in the putative anticancer effects of SSRIs in prostate cancer. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay assessed the antiproliferative effects of SSRIs and drug combinations. Cell death mechanisms were studied using annexin V-FITC/PI staining, and the cell cycle analysis was carried out by counterstaining with propidium iodide. Relative gene expression was assessed using a real-time polymerase chain reaction (PCR). Computational results hypothesized that SSRIs could potentially exert anticancer effects in prostate cancer cell lines by modulating apoptotic and tumorigenesis pathways and significantly inhibiting the growth of prostate cancer cells in a time and concentration-dependent manner. The combination of SSRIs with cisplatin, 5-fluorouracil, and raloxifene resulted in either synergistic or additive effects. SSRIs resulted in a significant increase in the early and late apoptotic activity in PC3 cells. Dapoxetine, paroxetine, and sertraline resulted in cell cycle arrest at the G0/G1 phase. Treatment with either dapoxetine or paroxetine decreases the expression of Bcl-2, CASP8, DR5, and VEGF. At the same time, sertraline decreases the expression of Bcl-2 and VEGF and increases the expression of CASP8 and DR5. Results revealed that SSRIs can potentially act as antiproliferative agents against prostate cancer cells, and their activity is mediated through different signaling pathways.

Membrane proteins (MPs) are important yet challenging targets for drug discovery. MPs can be reconstituted in protein‐lipid Nanodiscs (NDs), which resemble the native membrane environment. Drug‐membrane interactions can affect the apparent binding stoichiometry and affinity, as well as the kinetics of ligands for a particular target, which is important for the extrapolation to pharmacokinetic studies. To investigate the role of the membrane, we have applied fragment‐based drug discovery (FBDD) methods to cytochrome P450 3A4 (CYP3A4), reconstituted in NDs composed of different phosphocholine lipids: 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC), 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or 1,2‐diphytanoyl‐sn‐glycero‐3‐phosphocholine (DPhPC). Surface plasmon resonance screening of fragments and marketed drugs revealed extensive binding to the empty ND, correlating with analyte hydrophobicity, and the binding was critically dependent on ND lipid composition. POPC NDs showed much higher binding of fragments than DMPC and DPhPC NDs, resulting in a lower hit rate for CYP3A4 in POPC NDs, which demonstrated that the choice of the ND lipid is crucial to the outcome of a screen. The number of binders that were rejected based on atypical binding kinetics was lower for monomeric CYP3A4 in NDs than for non‐native oligomeric CYP3A4 without the ND. Several fragments were exclusively identified as hits for CYP3A4 in the presence of the ND membrane. It is concluded that the nature of the ND is a critical factor for fragment screening of membrane proteins.