Virtual library enumeration

Computational library design process begins with reagent selections, followed by diversity analysis and virtual library enumeration, and ends with selection of a final set of molecular structures to be synthesized (Fig. 9.4). Two databases, Available Chemical Database (ACD) (2) and Chemicals Available for... 

Figure 7.7 Combinatorial molecule assembly scheme. Resultant candidate molecules are objects that have building-blocks attached to scaffolds via linkers. Three user-definable fragment sets are needed to feed the algorithm with fragments for each domain. A few example fragments of each type are shown for clarity. For virtual library enumeration, each database fragment gets linked to each other fragment following a combinatorial assembly scheme.

Step 11 Build virtual library enumeration (to get new molecules that are not used for training)... 

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. 

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). 

Once the reactant pools have been filtered, the next step in product-based designs is usually to enumerate the full virtual library. This can be a very time-consuming step and hence a useful precursor can be to enumerate carefully chosen subsets that will give an indication of the success or otherwise of the full virtual experiment. Thus, in a two component reaction it can be useful to take the first reactant in the first pool and combine it with all the reactants in the second pool (to generate 1 x nB products). This should then be followed by the enumeration of one reactant in the second pool with all reactants in the first pool to give nA x 1 products. If either of these two partial enumeration steps fail, then the full enumeration will also fail. Thus, troublesome reactants can be identified early. 

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)... 

Next, we used an in-house library design software (see details in Chapter 15) to enumerate the virtual libraries and then calculated various physical properties. Products were removed from consideration if MW is > 300, number of rotatable bonds > 3, and ClogP > 3. For solubility, two in-house model calculations were applied as filters turbidimetric >10 mg/mL and thermodynamic solubility >100 xM. The resulting cherry-picked library was then reviewed by NMR spectroscopists to remove compounds with possible artifacts, likely to be insoluble, or likely to be false positive. These included some conjugated systems and compounds with likelihood of indistinct NMR spectra. 

Construction of a fully enumerated virtual library space (VL) for the second validation study... 

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... 

Figure 9.19 Physical property distributions of the fully enumerated virtual library. The average (AVG) and standard deviation (STD) are also provided for each of the four property distributions.

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