Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method

Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, a calcium channel overexpressed in breast and prostate cancer, and its use to test the effect of blocking TRPV6-mediated Ca2+-influx on cell growth. The inhibitor was discovered through a computational method, xLOS, a 3D-shape and pharmacophore similarity algorithm, a type of ligand-based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule, two successive rounds of LBVS followed by optimization by chemical synthesis led to a selective molecule with 0.3 μM inhibition of TRPV6. The ability of xLOS to identify different scaffolds early in LBVS was essential to success. The xLOS method may be generally useful to develop tool compounds for poorly characterized targets.

Three-State Single-Molecule Naphthalenediimide Switch: Integration of a Pendant Redox Unit for Conductance Tuning

We studied charge transport through core-substituted naphthalenediimide (NDI) single-molecule junctions using the electrochemical STM-based break-junction technique in combination with DFT calculations. Conductance switching among three well-defined states was demonstrated by electrochemically controlling the redox state of the pendent diimide unit of the molecule in an ionic liquid. The electrical conductances of the dianion and neutral states differ by more than one order of magnitude. The potential-dependence of the charge-transport characteristics of the NDI molecules was confirmed by DFT calculations, which account for electrochemical double-layer effects on the conductance of the NDI junctions. This study suggests that integration of a pendant redox unit with strong coupling to a molecular backbone enables the tuning of charge transport through single-molecule devices by controlling their redox states.

Psychotherapieforschung - Ist «Dodo Bird» en vogue?

Das «Dodo-Bird-Verdikt», Ende der achtziger Jahre Resultat einer Metaanalyse, stellte fest, dass sich die etablierten Psychotherapieschulen in ihrer Wirksamkeit statistisch nicht bedeutsam unterscheiden. Der Begriff hat seinen Ursprung in «Alice im Wunderland», wo ein Dodo den Vorschlag macht, ein Rennen zu veranstalten, bei dem am Ende alle gewinnen, weil es kein Ziel gibt und auch die Zeit nicht gemessen wird. – Ist die These unter Akteuren der Psychotherapie en vogue? Ein Kommentar.

Sprache – Macht – Geschlecht

Sprache, Macht und Geschlecht hängen zweifach zusammen. Sprache macht Geschlecht – vergessen wir nicht, dass Macht mit "vermögen" und "machen" zu tun hat – und Sprache konstitutiert Machtbeziehungen zwischen den Geschlechtern mit. Mit beidem befasst sich die Sprachwissenschaft seit den 1970er Jahren.