Fragment spaces have proven to be a valuable source of molecules that are biologically active and synthetically feasible. A fragment space consists of a set of molecular fragments with defined linking positions and a set of rules to combine fragments to new molecules.

We have developed an expert system for medicinal chemists to allow to search fragment spaces for molecules that can fulfill a chosen three dimensional pharmacophore. The fragment space is searched with an evolutionary approach, where partial solutions evolve to fit the posed query by adding, deleting of replacing fragments. The fitness of a partial solution is calculated by its ability to obey to the constraints of the pharmacophore.

We tested the program by searching several focused fragment spaces with pharmacophores for common drug targets. The resulting molecules obey to the input pharmacophore and look chemically sound.

Virtual screening is widely established as part of the drug discovery process. So far, the primary domain of application are screening collections based on in-house repositories and vendor catalogs, while pharma companies have access to large numbers of validated chemistries. It would be of great interest to perform virtual screens based on all compounds that are synthetically accessible by any such combinatorial library protocol. However, the number of possible compounds easily exceeds – by many orders of magnitude – the number of compounds that can be stored and searched by conventional methods.

We overcame these limitations by converting large numbers of combinatorial libraries into a "virtual chemistry space". FTrees is capable of searching such spaces for similar molecules and FlexNovo can retrieve virtual products on the basis of their fit to a protein active site. In each case compounds are suggested which are synthetically accessible via one or more of the existing synthetic routes. Such output provides library design ideas for hit follow-up from high-throughput screening or lead hopping into novel series. The design of a free publicly available chemistry space and a number of successful applications will be presented.

Chemists are well trained in perceiving 2D molecular sketches. On the side of computer assistance, the automated generation of such sketches becomes very difficult when it comes to multi-molecular arrangements such as protein-ligand complexes in a drug design context.

During the last few years we have developed PoseView, a tool which displays molecular complexes incorporating a simple, easy-to-perceive arrangement of the ligand and the amino acids to which it forms interactions. Resulting in atomic resolution diagrams, PoseView operates on a fast tree re-arrangement algorithm to minimize crossing lines in the sketches. Due to a de-coupling of interaction perception and the drawing engine, PoseView can draw any interactions, such as hydrogen bonds, metal interactions, pi interactions and undirected hydrophobic contacts, determined by either distance-based rules or the FlexX interaction model. Owing to the small-molecule drawing engine 2Ddraw, molecules are drawn in a textbook-like manner following the IUPAC regulations.

Besides the novel underlying interaction models, we will present new algorithmic approaches, assess usability issues and a large-scale validation study on the PDB.

Lead discovery often starts from small fragment binders for which experimental evidence has been found in an active site. Development into a lead structure can involve three possible scenarios: a) to grow from these 'needles' into the depth of the pocket; b) linkage of two or more fragments into one compound with optimized potency; or c) merging two or more fragments in regions of mutual overlap.
These tasks can now be accomplished with a novel software tool, which comprises the interactive fragment based software ReCore and the well established docking engine FlexX. With ReCore, synthetically accessible compounds can be generated in seconds by using an indexed 3D fragment library on fragments or compounds that should be altered. The results can then be validated by docking without leaving the software environment.

We will elucidate the basic principles and give examples which map onto experimental data and evolve into novel lead ideas.

An often encountered scenario in FBLD is experimental evidence of one or multiple fragment binders in a protein binding site. Typically, depending on quality and amount of information, subsequent steps can be divided into three classes: a) growing from these 'seeds', b) linking of two or more fragment binders, or c) merging multiple overlapping binders into a single potent lead.

To accomplish these tasks with ultimate efficiency, the software tool ReCore[1] has been developed. Based on a vast 3D fragment library, ReCore finds fragments which provide an optimal fit with the 'dangling bonds' and comply with optional filters and pharmacophore features. Based on a novel indexing technology, ReCore, in contrast to other tools targeting a similar challenge, provides its results within seconds, thus allowing interactive usage.

Synthetic access of results (which was a major weakness in the early days of de novo design) is taken care of in ReCore at three levels: during fragment creation, within query definition, and when creating the results. We will elucidate the basic principles and give examples which map onto experimental data and evolve into novel lead ideas.