De Novo design with Cosmos™
Cosmos™ is an acronym for Computational Optimization of Small Molecular Structures. It is a highly flexible in silico platform, based on a genetic algorithm for the evolution of molecules guided by one or more evaluation functions and fragment-based virtual synthesis. Evaluation functions can be ligand- and target-based.
As in a classical in vitro setup, Cosmos™ is build round three main blocks: virtual synthesis, evaluation or virtual screening, and optimization. The process is illustrated in the flowchart above. In the virtual synthesis step, de novo molecules are developed from a set of predefined building blocks and connectivity rules. Both building blocks and connectivity rules have been extracted from known compounds. As such, the possibility that the virtual compounds actually are synthesized in a later stage is rather high. In the next step, the molecules are evaluated using a virtual screening function. The evaluation of the molecule can be based on any kind of function and is completely flexible to meet the project needs. Typical evaluators that have been tested, are docking, shape-based similarity, fingerprint similarity, and Spectrophore™ models. The optimization step can be either a single- or multi-objective optimization depending on the number of targets and different scoring functions. From the scores, molecules are selected for further participation in the evolutionary process. Genetic operators, like mutation and crossover, have been implemented again using the same building blocks and connectivity rules as defined in the virtual synthesis. This closes the loop and the process restarts.
Example
To illustrate the potential of Cosmos™, cisapride has been used as a test case. The crystal structure of cisapride was used a template structure and new virtually synthesised compounds were compared with the template using a shape-based scoring function.
| Initial fit | Final fit |
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| Figure 1. Example of the evolutionary process in Cosmos™. The left image is a molecule found in the initial phase of the procedure. The molecule on the right is the best scoring molecule after 1000 generations. | |
The evolution of the molecules generated with Cosmos™ and their fit with the cisapride template is illustrated in this (quicktime movie, 5.4Mb).
Facts sheet
Leaflet (PDF).