Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (Kiapp of 7±2.4 µM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (Kiapp of 3.8±0.8 µM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors

Thermal effects in high density polyethylene and low density polyethylene at high hydrostatic pressures

The temperature changes as a result of rapid hydrostatic pressure applications are reported for high density polyethylene (HDPE) and low density polyethylene (LDPE) in the reference temperature range from 298 to 423 K and in the pressure range from 13.8 to 200 MN m −2 . The adiabatic temperature changes were found to be a function of pressure and temperature. A curve fitting analysis showed that the empirical curve (∂/∂ P ) = ab (Δ P ) b−1 described the experimental thermoelastic coefficients obtained from the experiments. The data were analyzed by determining the predicted thermoelastic coefficients derived from the Thomson equation (∂/∂ P ) θ = α T 0 /ϱ C p . The experimental and predicted Grüneisen parameter γ T were also determined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44687/1/10853_2005_Article_BF01132919.pd