We often run virtual screening projects for clients. The usual result is a list of compounds to make or purchase. However, procurement can be quite a difficult project in itself with many trade-offs between availability, diversity, cost and convenience.
Cresset Discovery manage the procurement process for you, delivering plated, assay-ready compounds to your lab. We balance the cost per compound against the accessibility and the novelty of the compound. Then we provide a list of the most cost effective set of compounds that would best explore the potentials of the hits.
We optimize the compound selection process so that you get the best possible selection of compounds delivered to the next stage in the discovery process. Working with best- in-class chemistry and shipping providers, we provide you with a single point of contact so that you end up with not only the answers you want, but also the actual compounds.
Cresset’s virtual screening database contains over 10 million compounds with 6.4 million unique structures from over 20 different vendors. We restrict our collection to real compounds with physical samples that can be immediately sourced from vendors, as opposed to including compounds that have not yet been synthesized. The database is kept continually up to date from the catalogues and is a comprehensive source of available screening compounds.
We load the compounds into the database in the form of SMILES strings or SD files. In order to make this database searchable using our virtual screening platform Blaze, each 2D compound is expanded to a set of 3D conformations. These are minimized and up to 100 conformers are stored for each compound. Fields are added to each conformer, enabling it to be compared to the query molecule for a potential match.
This database gives our customers a very broad selection of chemistry, as opposed to screening compounds from only one vendor. The downside is that the final results of a virtual screen may be 500 compounds from 20 different vendors, possibly with only a handful of compounds coming from some vendors. This leads to bureaucratic and shipping overheads. Each vendor charges a fixed amount per compound, plus a flat rate shipping fee, therefore the more compounds sourced per vendor, the cheaper the final total. Multiple vendors also need multiple legal agreements.
Example KNME™ workflow for the ordering of compound from a virtual screening campaign
Cresset can help to deal with logistic difficulties in two ways. The first is to compare the results and suggest the same or very similar compounds from alternative vendors in order to reduce the number of vendors in the final list of compounds. The second is for us to handle the procurement process for you. We set up the agreements with each of the vendors so that is not a legal bind for the client. We set up the agreements with each of the vendors, choose the compounds, substitute the next best compound according to cost or availability and arrange the shipping.
Recently we worked with a customer who came to us with a known target. They had a number of published active compounds and were looking for some new chemistry for some assays they had booked with a biology CRO.
Our virtual screening work resulted in recommendations for 250 screening compounds. For additional diversity, we used Spark to do bioisosteric replacements around the core of the known active compounds. We used these new bioisosteres for a further virtual screen and used these results to recommend a further 50 compounds.
Further work was then done to optimize the selection of compounds by looking at both alternative vendors for the same compounds and highly similar compounds from alternative vendors. Where we had found very few compounds from one vendor, we identified alternatives from larger suppliers. At the end of this process we reduced the number of vendors for the 300 compounds from about 10 to 6. Of those 300, approximately 200 were sourced from only 2 vendors.
The customer chose to completely outsource the procurement of these compounds to Cresset Discovery.
Cresset Discovery managed the process, using a dedicated chemistry provider and specialist shipping agents. The compounds were purchased from the various vendors, weighed, dissolved, plated and delivered to the biology CRO to be screened. The compound procurement for this project was multi-national, including the UK, Europe, Eastern Europe and the US. The final delivery was to a California-based biology CRO.
Not only did we recommend new compounds, we delivered the final plates to the biology CRO.
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