Virtual enumeration

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. 

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

Preparation of virtual screening databases starts with standardization of the input SMILES. This procedure was originally developed to deal with databases from commercial suppliers. Preferred tautomeric forms are generated in this step and ionized species are neutralized. Ionization states are set in the second step for biased equilibria and multiple forms are enumerated in a third step to represent balanced equilibria. The model treats an equilibrium as balanced if the equilibrium constant associated with its defining rule is likely to be less than about 1.5 log units. 

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)... 

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... 

PGVL Hub for reactant monomer retrieval, virtual product enumeration, molecular property calculation, product property profiling, and exporting virtual product structures for subsequent docking... 

Enumerate the virtual products for the alcohol template and the selected amines using the PGVL Hub virtual product enumerator. 

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. 

---