Screening a Virtual Compound Space
From virtual screening to de novo drug design, there is a wide spectrum of tools available for computer aided drug discovery. The methods developed have their strengths as well as their weaknesses. On one end of the spectrum virtual screening techniques, for instance, are fast and guarantee the availability of virtual hits for in vitro tests. However, the set of available chemicals is limited (10 000 000 is probably a good upper estimation for the number of known chemicals) and this implies a limited usability of virtual screening.
Towards the other end of the spectrum of discovery tools de novo drug design methods try to alleviate the problem of a finite compound space by suggesting novel molecular structures. Often, these are assembled by linking small molecular fragments in a procedure which is more or less chemically unaware. As a consequence the synthetic accesibility of de novo designed ligands is often a problem.
A method, which combines advantages of virtual screening with advantages of de novo design while eliminating their disadvantages has been implemented. This method deploys virtual screening over an ever growing space of virtual compounds that are likely to be synthetically accessible. To achieve this, commercially available chemical structures are combined by smart chemical reactions . These, unlike generic reaction equations that generate all possible products that are topologically relevant, are capable of eliminating products that are unlikely to be accessible via chemical synthesis.
In addition to synthetic accessibility there is another advantage of this method: no design is involved during structure generation. Consequently structures will be diverse both chemically and biologically and they can be screened for various targets simultaneously or at a later time so no potential lead is lost.
The applicability and efficiency of the method will be demonstrated with various examples.