Hit follow

Fig. 2.2. Three components of a typical VS process compound library, virtual assay, and hit follow-up for virtual hits.

Hit follow-up consideration was accounted for via two filters to remove undesirable functional groups and to include molecules with a desirable functional group that would act as chemistry handles to enhance compound elaboration. These filters were derived from extended discussion with medicinal chemists. A total of 12 undesirable functional group sets were created and collectively used as a negative filter ... 

Estep, K. (2004) File Enrichment and Hit Follow Up Evolution and Examples. Poster Presentations at the ALA LabPusion. 

Smith, G. F. (2006) Enabling HTS Hit follow-up via Chemo informatics, File Enrichment, and Outsourcing. High Throughput Medicinal Chemistry II MMS Conferencing 8c Events Ltd., Institute of Physics London. This article is also available on-line via this web link (http //www.mmsconferencing.com/pdf/ htmc / g. smith. pdf). 

Another important component of the protein dossier is structural information. Do high-resolution structures (either NMR or X-ray) exist that can be used for library generation and hypothesis testing/generation112,41-441 Are these structures with bound ligands In many medicinal chemists eyes, this is the most important of the criteria in fact, to many it is so important that hit follow-up will not be pursued until suitable structures are in hand. Several companies entire business model is based upon X-ray-based screening of fragment libraries. 

Second-hit hypothesis This hypothesis has been proposed as a plausible explanation for the occurrence of NASH. (48, 70) The first hit is considered to be the development offatty liver, particularly due to hyperahmentation and obesity resulting in insulin resistance. As second hit follows the mobilization of free fatty acids from fat depots and their transport to the liver cells. This leads to a massive increase of free radicals due to oxidative stress with lipid peroxidation and induction of cytokines (TNFa, TGFp, IL6, IL8). As a result, there is a reactive formation of uncoupling protein (UCP2) with a subsequent decrease in hepatocyte ATP and a disturbance of macrophage function with higher sensitivity to endotoxin. This leads to an inflammatory reaction, cell death and the formation of fibrosis. (44, 50, 65)... 

Preliminary hit follow-up was accomplished by performing similarity searches on databases of commercially available analogues (Fig. 2). In this initial phase, 50 commercial analogues were identified, purchased, and tested for their ability to inhibit TNAP. This allowed us to define some important features of the SAR. For example, the potency in this series was improved from IC5o = 0.98 pM for the lead pyrazole 1 to IC5o = 0.50 pM for the... 

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