Combinatorial libraries enumeration

Schuller, A., Hahnke, V, Schneider, G. (2007) SmiLib v2.0 a Java-based tool for rapid combinatorial library enumeration QSAR. Comb Sci 26, 407-110. 

Schuller A, Hahnke V, Schneider G (2007) SmiLib v2.0 A Java-Based Tool for Rapid Combinatorial Library Enumeration. QSAR Comb Sci 3 407-410... 

The term enumeration when applied to a combinatorial library refers to the process by which the cormection tables for the product structures in a real or virtual library are produced. It should be noted that a single compound can be considered as a library of one and so enumeration can equally well be applied in this case. However, whereas it is considered reasonable for a chemist to draw the structure of a single compoimd manually (which may have taken days, if not months or years, to synthesise), it is clearly not practical to do so even for small combinatorial libraries. Hence the need for automated tools to perform this procedure. 

Fig. 15.24 RADDAR a nearly infinite number of chemical structures can be generated by computationally enumerating combinatorial library proposals. Cherry picking of interesting candidates (proposed structures) based on defined computational algorithms allows the chemist to synthesize the relevant subsets of theoretically accessible molecules.

Enumeration is the computational equivalent of carrying out a combinatorial synthesis. The result is a virtual library of product molecules that can then be analyzed using a library design program to select compounds of interest. Two different approaches to library enumeration have been developed fragment marking and the reaction-transform approach (14). 

Fig. 2.4. Product enumerations of a combinatorial library. For reaction-based enumeration, individual groups of —N(R1)(R2) and —(C0)-R3 are replaced by corresponding molecular fragments from reactants A and B. For template-based enumeration, the R-groups R1, R2, and R3 are replaced by independent lists of molecular fragments. Note that some combinations of R1 and R2 may not exist in component A for reaction-based enumerations. The template-based product structure with R-groups is also called Markush structure and its enumeration is called Markush enumeration or Markush exemplification.

Basis products (BPs) Exploits the redundancy of fragments in a combinatorial library and identifies a small subset of compounds (BPs) which represent the entire virtual library. BPs are docked, scored, and used for final library enumeration (85)... 

Key words Drug discovery, chem-informatics, molecular design, combinatorial chemistry, combinatorial library, synthesis protocol, PGVL, reactant, product, enumeration, filtering integration, workflow, streamline, desktop tool, software deployment. 

Having the desired reactant lists, the chemist can now create a virtual library by enumerating the product structures in a fully combinatorial manner. Enumeration instructions are prevalidated for all PGVL registered reactions for a user-specified reaction, PGVL Hub enables enumeration via the Markush representation of the reaction scheme. Once the products are... 

Control the size of the enumerated library As the name implies, combinatorial libraries can explode in size very quickly. Therefore one must perform reactant-level selections before product enumeration in most design cases. As shown in the example library, molecular weight (MW) is an effective filter to cut down number of reactants, so is reactant availability inside the reactant inventory system. As a matter of principle, more expensive computational approaches (e.g., protein-ligand docking and scoring) should be applied only to smaller subsets of reactants or products. 

CLEVER is a computational tool designed to support the creation, manipulation, enumeration, and visualization of combinatorial libraries. The system also provides a summary of the diversity, coverage, and distribution of selected compound collections. When deployed in conjunction with large-scale virtual screening campaigns, CLEVER can offer insights into what chemical compounds to synthesize, and, more importantly, what not to synthesize. In this chapter, we describe how CLEVER is used and offer advice in interpreting the results. 

Fig. 1. A combinatorial library represented as an R-group structure, and two enumerated structures.

On the other hand, the enumerated structures themselves might be useful as input for other computer programs that generate computational data, such as QSAR or other chemical property predictions. Since these programs accept and work on individual specific structures, these structures must be generated both for input to these programs and for association with their output. This capability is important for the process of designing new combinatorial libraries. 

There might often be cause to limit the enumeration to less than every possible specific structure or subgeneric structure represented by the combinatorial library. If the library represents a real experiment, then perhaps not every combination of R-group members represents a compound that was actually synthesized. If the library is to be enumerated... 

Enumerating the product space of combinatorial libraries and calculating the descriptors can be expensive computationally. Recently, Downs and Barnard [62] have described an efficient method of generating fingerprint descriptors of the molecules in a combinatorial library without the need for enumeration of the products. This method is based on earlier technology for handling Markush structures. An alternative approach is to use random sampling techniques to derive a statistical model of the property under consideration [63],... 

Combinatorial chemistry (Combi Chem) Used to make thousands of variants of a compound. Consider a compound with a six-membered aromatic ring and a chlorine atom attached at a certain position. One might change the location of the chlorine to any of the other five positions, or change the chlorine to a fluorine or a bromine, and/or make the same changes at all the other five positions. To enumerate all the possible combinations is to make a combinatorial library. 

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