4a. Introduction
Back to the Combinatorial Chemistry Methodologies index.
Accessing the combinatorial chemistry modules
Once the Cerius2 software has been installed and licensed and your system set up (see Start-up and Configuration), access the Cerius2 Combinatorial Chemistry Software Suite by going to a UNIX shell and entering:
> cerius2
Once Cerius2 has started, you use the COMBI-CHEM decks to run diversity experiments. The Combinatorial Chemistry Software Suite is found in the COMBI-CHEM I and COMBI-CHEM II decks of cards.
COMBI-CHEM I contains these cards:
COMBI-CHEM II contains these cards:
Planning the diversity experiments
Reagent selection
Reagent selection is often the first attempt at the design of diverse libraries. Several advantages to diverse reagent selection are:
However, what finally matters is the selection of products that are submitted for screening, hence some fundamental drawbacks of simple reagent selection:
Planning the diversity experiment requires a clear understanding of the chemistries that are available to you. The flexibility (or lack thereof) of your robotics installation towards noncombinatorial approaches will also guide your choice. You then decide if your objectives are simple reagent selection, noncombinatorial product selection or combinatorial product selection (selection of reagents based on product diversity).
Parallel synthesis
Parallel synthesis is often a solution chemistry process by which individual molecules may be made in an efficient manner. The access to individual structures provides some key advantages:
Parallel synthesis also suffers some drawbacks that are mostly related to the experimental procedures:
Combinatorial synthesis
Combinatorial synthesis proceeds from a strict matrix of reagents that are carried through the several steps of the synthesis process. This procedure is often preferred for several reasons:
The strict combinatorial approach still suffers some drawbacks, specially in relation to the collection of product obtained:
New semicombinatorial techniques have emerged where penalties are applied to the design when noncombinatorial products are selected. Again, given the differences in equipment, high flexibility is required from these advanced techniques.
Lead discovery
In the lead discovery or lead generation phase, one may proceed from an available collection of compounds or by designing a combinatorial library (a screening library). In either case, the overall goal is to maximize the chemical diversity of the compound collection or library while keeping it at an experimentally practical size.
The reasoning behind this approach is that, in general, chemically diverse compounds provide a more efficient sampling of "chemistry space" than a library composed of randomly selected models.
Optimization
After lead compounds with moderate activities have been found, the overall goal in the subsequent lead follow-up phase is to find compounds that resemble the lead compounds. This may be done by searching databases of commercially available compounds or by designing focused libraries around the original lead compounds. One can thus explore variations in chemical and molecular properties and increase the chances of finding more active models in secondary screening rounds.
Last updated May 19, 2000 at 01:51PM Pacific Daylight Time.
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