10 research outputs found
Escherichia coli l-aspartate-α-decarboxylase: preprotein processing and observation of reaction intermediates by electrospray mass spectrometry
OPSM - Opportunistic Power Save Mode for infrastructure IEEE 802.11 WLAN
We focus on the energy spent in radio communication by the stations (STAs) in an IEEE 802.11 infrastructure WLAN. All the STAs are engaged in web browsing, which is characterized by a short file downloads over TCP, with short duration of inactivity or think time in between two file downloads. Under this traffic, Static PSM (SPSM) performs better than CAM, since the STAs in SPSM can switch to low power state (sleep) during think times while in CAM they have to be in the active state all the time. In spite of this gain, performance of SPSM degrades due to congestion, as the number of STAs associated with the access point (AP) increases. To address this problem, we propose an algorithm, which we call opportunistic PSM (OPSM). We show through simulations that OPSM performs better than SPSM under the aforementioned TCP traffic. The performance gain achieved by OPSM over SPSM increases as the mean file size requested by the STAs or the number of STAs associated with the AP increases. We implemented OPSM in NS-2.33, and to compare the performance of OPSM and SPSM, we evaluate the number of file downloads that can be completed with a given battery capacity and the average time taken to download a file
Novel Chemoselective Linkage Chemistry toward Controlled Loading of Ligands to Proteins through In Situ Real-Time Quantification of Conjugate Formation
Continuous-flow injection microfluidic thrombin assays: The effect of binding kinetics on observed enzyme inhibition
The Use of Fluorogenic Substrates to Monitor Thrombin Generation for the Analysis of Plasma and Whole Blood Coagulation
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Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform
Hepsin
is a membrane-anchored serine protease whose role in hepatocyte growth
factor (HGF) signaling and epithelial integrity makes it a target
of therapeutic interest in carcinogenesis and metastasis. Using an
integrated design, synthesis, and screening platform, we were able
to rapidly develop potent and selective inhibitors of hepsin. In progressing
from the initial hit <b>7</b> to compound <b>53</b>, the
IC<sub>50</sub> value against hepsin was improved from ∼1 μM
to 22 nM, and the selectivity over urokinase-type plasminogen activator
(uPA) was increased from 30-fold to >6000-fold. Subsequent <i>in vitro</i> ADMET profiling and cellular studies confirmed
that the leading compounds are useful tools for interrogating the
role of hepsin in breast tumorigenesis
Integrated Synthesis and Testing of Substituted Xanthine Based DPP4 Inhibitors: Application to Drug Discovery
A novel
integrated discovery platform has been used to synthesize
and biologically assay a series of xanthine-derived dipeptidyl peptidase
4 (DPP4) antagonists. Design, synthesis, purification, quantitation,
dilution, and bioassay have all been fully integrated to allow continuous
automated operation. The system has been validated against a set of
known DPP4 inhibitors and shown to give excellent correlation between
traditional medicinal chemistry generated biological data and platform
data. Each iterative loop of synthesis through biological assay took
two hours in total, demonstrating rapid iterative structure–activity
relationship generation
Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform
Drug
discovery faces economic and scientific imperatives to deliver
lead molecules rapidly and efficiently. Using traditional paradigms
the molecular design, synthesis, and screening loops enforce a significant
time delay leading to inefficient use of data in the iterative molecular
design process. Here, we report the application of a flow technology
platform integrating the key elements of structure–activity
relationship (SAR) generation to the discovery of novel Abl kinase
inhibitors. The platform utilizes flow chemistry for rapid in-line
synthesis, automated purification, and analysis coupled with bioassay.
The combination of activity prediction using Random-Forest regression
with chemical space sampling algorithms allows the construction of
an activity model that refines itself after every iteration of synthesis
and biological result. Within just 21 compounds, the automated process
identified a novel template and hinge binding motif with pIC<sub>50</sub> > 8 against Abl kinase î—¸ both wild type and clinically
relevant
mutants. Integrated microfluidic synthesis and screening coupled with
machine learning design have the potential to greatly reduce the time
and cost of drug discovery within the hit-to-lead and lead optimization
phases
Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery
The Plasmodium falciparum cysteine peptidases FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases and are therefore potential anti-malarial drug targets. To facilitate a rational drug discovery programme, in the current study we analysed the synthetic substrate and model inhibitor profiles of FP-2 and FP-3 as well as BP-2 (berghepain-2), an orthologue from the rodent parasite Plasmodium berghei. With respect to substrate catalysis, FP-2 exhibited a promiscuous substrate profile based around a consensus non-primeside motif, FP-3 was somewhat more restricted and BP-2 was comparatively specific. Substrate turnover for FP-2 was driven by a basic or acidic P1 residue, whereas for FP-3 turnover occurred predominately through a basic P1 residue only, and for BP-2, turnover was again mainly through a basic P1 residue for some motifs and surprisingly a glycine in the P1 position for other motifs. Within these P1 binding elements, additional recognition motifs were observed with subtle nuances that switched substrate turnover on or off through specific synergistic combinations. The peptidases were also profiled against reversible and irreversible cysteine peptidase inhibitors. The results re-iterated the contrasting kinetic behaviour of each peptidase as observed through the substrate screens. The results showed that the substrate and inhibitor preferences of BP-2 were markedly different from those of FP-2 and FP-3. When FP-2 and FP-3 were compared to each other they also displayed similarities and some significant differences. In conclusion, the in vitro data highlights the current difficulties faced by a peptidase directed anti-malarial medicinal chemistry programme where compounds need to be identified with potent activity against at least three peptidases, each of which displays distinct biochemical traits