Experiences in fragment-based drug Discovery // Drug Repurposing

Experiences in fragment-based drug Discovery

Screening library size

This post got prompted by a survey of screening library size by Teddy at Practical Fragments. I commented briefly there but it soon became clear that it was going to take a really long comment to say everthing. While at AstraZeneca, I was involved in putting together a 20k screening library for fragment-based work and I thought that some people might be interested in reading about some of the experiences. The project started at the beginning of 2005 although the library (GFSL2005) was not assembled until the folllowing year. Some aspects of the library design were also described in our contribution to the JCAMD special issue on FBDD. ? One reason was diversity of fragment-based activities, which included a high concentration component when running HTS In screening, you soon learn the importance of logistics and, in particular, compound managment. If you're going to assemble a screening library that can be easily used, this usually means getting the compounds into dimethyl sulfoxide (DMSO) so that samples can be dispensed automatically. Fragments will usually be screened at high concentration which means that stock solutions also need to be more concentrated (we used 100µM) because most assays don't particularly like DMSO. Another reason for maintaining stock solutions is that there are minimum volume limits for dissolving solids in DMSO so starting from solids each time you run a screen is wasteful of material as well as time. The essence of the GFSL2005 project was ensuring that there were enough high concentration stock solutions in the liquid store to support diverse fragment-based activities on different Discovery sites. While the entire library might be screened as a component of HTS, individual groups could screen subsets of GFSL05 that were significantly smaller (at least when I left AZ in 2009). It's important to rememember that while GFSL05 was a generic library we were also trying to anticipate the needs of people who might be doing directed fragment screening. The compounds were selected using Core and Layer (which I've discussed before). This approach is not specific to fragment screening libraries and I've used it to put together a compound library for phenotypic screening. The in house software, some of which had been developed in response to emergence of HTS, was actually in place by the beginning of 1996. Here (from one of my presentations) is a slide that illustrates the approach. One of the...

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by invivoVibrio

I have worked in several labs that have produced, either directly or through a spin-off company, real products that are medically useful. Scientists are the ones who create vaccines, design diagnostic devices and tests, and discover useful drugs.
There's a whole spectrum that falls under the title "science," which ranges from the purely discovery-oriented, focusing on just learning more about a topic for learning's sake; to the purely practical, such as so-called translational research, where scientists iron out the details of a practically useful discovery and optimize it for practical applications, "translating" the basic science into something that can be produced and sold by industry

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Ohio State, through the Ohio State Innovation Foundation and the university's Drug Development Institute, and the University of Michigan licensed the intellectual property to the newly formed Sirona Therapeutics.

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Academic Press Structural and Mechanistic Enzymology:, Volume 87: Bringing Together Experiments and Computing (Advances in Protein Chemistry)
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