Identification of potent and selective inhibitors of PKR via virtual screening and traditional design.

Protein Kinase RNA-activated (PKR) inhibition is thought to be relevant for immunology due to the potential to reduce macrophage and dendritic cell responses to bacteria and its signaling downstream of TNFα. PKR is also associated with neuroscience indications such as Alzheimer's disease due to its activation by the double stranded DNA (dsDNA) virus HSV1, a virus suggested to be important in the development of AD. Studies exploring the mechanistic role of PKR with existing tool molecules such as the tricyclic oxindole C16 are clouded by the poor selectivity profile of this ATP-competitive, Type I kinase inhibitor. Type II kinase leads such as the benzothiophene or pyrazolopyrimidine scaffolds from literature are equally poor in their selectivity profiles. As such, it became necessary to identify more potent and selective chemical matter to better understand PKR biology. A dual approach was taken. The first step of the strategy included virtual screening of the AbbVie compound collection. A combination of pharmacophore-based and GPU shape-based screening was pursued to identify selective chemical matter from promiscuous leads. The second step of the strategy followed traditional compound design. This step initiated from a literature lead with PKR cross reactivity. Combined, the two parallel efforts led to identification of more selective leads for investigation of PKR biology.

Effects of the degradation rate of collagen matrices on articular chondrocyte proliferation and biosynthesis in vitro.

The objective of this study was to evaluate effects of the degradation rate of type II collagen scaffolds on the proliferation and biosynthetic activity of adult canine chondrocytes in vitro. The lower number of cells in more rapidly degrading scaffolds appeared to be related to the loss of scaffold material with dissolution. After 14 days in culture, protein and proteoglycan synthesis rates per cell for rapidly degrading scaffolds were comparable to rates for nondegraded matrices. This result suggests that decoupling of the degradation and formation phases of tissue remodeling may occur under certain circumstances.