CAESA: Computer Assisted Estimation of Synthetic Accessibility

Method

The program uses the technology of expert systems to mimic methods used by an experienced synthetic chemist to estimate the ease of synthesis of a particular compound. Potential starting materials are selected from databases of available compounds and the structural features that make a compound difficult to synthesize are identified. The combination of these two types of information provides a realistic estimate of the likely ease of synthesis. The program comprises a set of modules which estimate synthetic accessibility using a knowledge based approach.

New techniques have been developed which permit rapid searches for potential starting materials within databases of available compounds (such as the Fine Chemicals Directory or in-house databases). Potential synthetic routes are established between all compounds in these databases and the target structures. The length and quality of each route is assessed and the best are selected. A series of efficient measures have been implemented to ensure the search is fast. The user is provided with structures of the potential starting materials along with information concerning the quality of the synthetic routes from individual starting materials.

The presence of complexity-enhancing structural features (such as chiral centres or complex topological features) is detected in each target molecule. These features are used to assess the ease of synthesis of a compound. Only features that are not contained within the selected starting materials are considered to contribute towards the synthetic difficulty of the compound. Recent developments in expert systems, Causal Networks, are used to combine the information from a variety of sources and calculate an index of synthetic accessibility.

The program uses two sources of information, that could be customized to provide estimations specific to the chemistry employed in the company:

1. a database of available starting materials and

2. a reaction knowledge-base. 

The database of available starting materials is customizable with a converter program provided in the CAESA package. This converter takes custom databases in MDL molfile format and converts them off-line into an internal CAESA format.  Extension of the reaction knowledge-base is a more manual process. There are about 180 basic reactions supplied with the program. The reactions are described in a pattern language called:  PATRAN, which  is an ASCII (human readable) pattern language designed specifically for reactions.  It is similar to the SMILES notation, but extended to handle reactions not only individual molecules. PATRAN also allows usage of generic atomtypes. The reaction knowledge base of CAESA is extendible by the user to include additional reactions specific to the chemistry applied in the company.