Computer-implemented method of merging libraries of molecules using validated molecular structural descriptors and neighborhood distances to maximize diversity and minimize redundancy
View Patent ↗The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets. By the appropriate application of validated metrics, the method of this invention selects a subset of a combinatorial accessible chemical universe such that the molecules of the subset are representative of all the diversity present in the universe and yet do not contain multiple members which represent the same diversity (oversample). The use of the neighborhood definition of a validated metric may also be used to combine (without oversampling the same diversity) any number of combinatorial screening libraries.
1. A computer implemented method of merging with a base assembly of molecules one or more additional assemblies of molecules, similar molecules in the assemblies having previously been identified and removed using a molecular structural descriptor validated as possessing a neighborhood property, comprising the steps of:
a) using a molecular structural descriptor, validated as possessing a neighborhood property, which is appropriate to whole molecules, characterizing all the molecules in the base assembly of molecules and in the assembly of molecules to be merged;
b) calculating the molecular structural distance between every molecule in the base assembly to every molecule in the assembly to be merged;
c) while there are still molecules in the assembly to be merged which have not been tested, selecting a molecule from the assembly to be merged;
d) determining whether the molecular structural distance between the selected molecule and every molecule in the base assembly is within the neighborhood distance of the molecular structural descriptor;
e) selecting for inclusion in the merged assemblies only those molecules identified in step d as having molecular structural distances greater than the neighborhood distance.
f) repeating step c through step e until all molecules in the assembly to be merged have been tested; and
g) repeating step a through step f for each additional assembly to be merged; and
h) outputting the merged assembly of molecules wherein the merged assembly of molecules has optimal diversity between and among its members.
2. The method of claim 1 in which the molecular structural descriptor, validated as possessing a neighborhood property, appropriate to whole molecules is the Tanimoto similarity coefficient.
3. A computer implemented method of merging with a base assembly of molecules one or more additional assemblies of molecules, similar molecules in one or more of the assemblies having not previously been identified and removed using a molecular structural descriptor, validated as possessing a neighborhood property, comprising the steps of:
a) selecting subsets of each assembly by:
(1) selecting a molecule within each assembly;
(2) using a molecular structural descriptor, validated as possessing a neighborhood property, appropriate to whole molecules, calculating the descriptor distance between the selected molecule and all molecules within the assembly;
(3) determining the shortest distance between the selected molecule and all molecules previously selected for the subset;
(4) selecting for inclusion in the subset the molecule whose shortest descriptor distance from the previously selected molecules is the largest and is greater than the neighborhood distance of the descriptor;
(5) repeating steps (1) through (4) until the largest shortest difference between molecules is less than the neighborhood distance of the descriptor; and
(6) repeating steps (1) through (5) for each assembly;
b) using a molecular structural descriptor, validated as possessing a neighborhood property, which is appropriate to whole molecules, characterizing all the molecules in the base assembly of molecules and in the assembly of molecules to be merged;
c) calculating the molecular structural distance between every molecule in the base assembly to every molecule in the assembly to be merged;
d) while there are still molecules in the assembly to be merged which have not been tested, selecting a molecule from the assembly to be merged;
e) determining whether the molecular structural distance between the selected molecule and every molecule in the base assembly is within the neighborhood distance of the molecular structural descriptor;
f) selecting for inclusion in the merged assemblies only those molecules identified in step e as having molecular structural distances greater than the neighborhood distance.
g) repeating step d through step f until all molecules in the assembly to be merged have been tested; and
h) repeating step b through step g for each additional assembly to be merged; and
i) outputting the merged assembly of molecules
wherein the merged assembly of molecules has diversity between and among its members and does not redundantly include molecules likely to share the same activity.