Among healthy subjects, risk allele homozygotes showed larger total WM volumes than carriers of the other allele. Controlling for WM volumes, these
same subjects showed reduced GM volumes in several regions comprising the ‘default mode network,’ including angular gyrus, parahippocampal gyrus, posterior cingulate, and medial orbitofrontal gyrus/gyrus rectus (FDR-corrected p<0.05). The risk allele dosage also predicted impairments on a timed visuomotor performance task (trails A). Results support a role of ZNF804A in phenotypes reflecting altered Omipalisib price neural connectivity. Neuropsychopharmacology (2010) 35, 2284-2291; doi:10.1038/npp.2010.102; published online 21 July 2010″
“Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as
a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease VX-661 complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to “”lock”" into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the
substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles GDC-0449 nmr with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.”
“A functionally hypoactive prefrontal cortex (PFC) is thought to contribute to decreased cognitive inhibitory control over drug-seeking behavior in cocaine addicts. Alterations in PFC dopamine (DA) and gamma-aminobutyric acid (GABA) transmission are involved in the development of behavioral sensitization to cocaine, and repeated exposure to cocaine decreases DA D2 receptor (D2R) function in the PFC.