https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:6906 Wed 11 Apr 2018 16:31:00 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27301 50 2.6±0.7µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.]]> Sat 24 Mar 2018 07:38:33 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:26825 in silico screening of novel transcription inhibitors. Here, we describe our approach for the design and testing of small molecule transcription inhibitors that work by preventing the interaction between the essential transcription initiation factor σ and RNAP. With the appropriate structural information this approach can be easily modified to other essential protein-protein interactions.]]> Sat 24 Mar 2018 07:36:25 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52505 Mon 16 Oct 2023 10:10:51 AEDT ]]>