Synthesis and Structure-Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents.

Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure-activity relationship of this novel non-steroidal compound class

Observing GRBs with the LOFT Wide Field Monitor

LOFT (Large Observatory For X-ray Timing) is one of the four candidate missions currently under assessment study for the M3 mission in ESAs Cosmic Vision program to be launched in 2024. LOFT will carry two instruments with prime sensitivity in the 2-30 keV range: a 10 m2 class large area detector (LAD) with a <1° collimated field of view and a wide field monitor (WFM) instrument. The WFM is based on the coded mask principle, and 5 camera units will provide coverage of more than 1/3 of the sky. The prime goal of the WFM is to detect transient sources to be observed by the LAD. With its wide field of view and good energy resolution of <500 eV, the WFM will be an excellent instrument for detecting and studying GRBs and X-ray flashes. The WFM will be able to detect ~150 gamma ray bursts per year, and a burst alert system will enable the distribution of ~100 GRB positions per year with a ~1 arcmin location accuracy within 30 s of the burst

A Steered Molecular Dynamics Study of Binding and Translocation Processes in the GABA Transporter

The entire substrate translocation pathway in the human GABA transporter (GAT-1) was explored for the endogenous substrate GABA and the anti-convulsive drug tiagabine. Following a steered molecular dynamics (SMD) approach, in which a harmonic restraining potential is applied to the ligand, dissociation and re-association of ligands were simulated revealing events leading to substrate (GABA) translocation and inhibitor (tiagabine) mechanism of action. We succeeded in turning the transporter from the outward facing occluded to the open-to-out conformation, and also to reorient the transporter to the open-to-in conformation. The simulations are validated by literature data and provide a substrate pathway fingerprint in terms of which, how, and in which sequence specific residues are interacted with. They reveal the essential functional roles of specific residues, e.g. the role of charged residues in the extracellular vestibule including two lysines (K76 (TM1) and K448 (TM10)) and a TM6-triad (D281, E283, and D287) in attracting and relocating substrates towards the secondary/interim substrate-binding site (S2). Likewise, E101 is highlighted as essential for the relocation of the substrate from the primary substrate-binding site (S1) towards the cytoplasm