Virtual library searchable for possible combinatorially derived product molecules having desired properties without the necessity of generating product structures
View Patent ↗The problem of how to select out of a large chemically accessible universe molecules representative of the diversity of that universe is resolved by the discovery of a method to validate molecular structural descriptors. Using the validated descriptors, optimally diverse subsets can be selected. In addition, from the universe, molecules with characteristics similar to a selected molecule can be identified. The validated descriptors also enable the generation of a huge virtual library of potential product molecules which could be formed by combinatorial arrangement of structural variations and cores. In this virtual library it is possible to search billions of possible product compounds in relatively short time frames.
1. A virtual library stored on computer readable medium of possible combinatorially derived product molecules generated by the following process:
a) creating one or more files identifying one or more combinatorial reactions for one or more core structures;
b) creating separate structural variation files (associated with the reaction identifying files) in which are listed together the structural variations representative of those reactants which will react at each variation site of each combinatorial reaction;
c) associating with each structural variation, data, characterizing each structural variation including:
1) characterizing data, taking into account when necessary the structures of the cores with which the structural variations would be combined in the listed combinatorial syntheses, which has not been derived from the application of molecular structural descriptors, validated as possessing a neighborhood property; and
2) characterizing data, taking into account when necessary the structures of the cores with which the structural variations would be combined in the listed combinatorial syntheses, which has been derived from applying molecular structural descriptors, validated as possessing a neighborhood property, to the structural variations
wherein the virtual library can be searched for product molecules having desired properties without the necessity of generating the product structures during the search.
2. A virtual library stored on computer readable medium of possible combinatorially derived product molecules generated by the following process:
a) creating one or more files identifying one or more combinatorial reactions for one or more core structures;
b) creating separate structural variation files (associated with the reaction identifying files) in which are listed together the structural variations representative of those reactants which will react at each variation site of each combinatorial reaction;
c) associating with each structural variation, data, characterizing each structural variation including:
(1) characterizing data, taking into account when necessary the structures of the cores with which the structural variations would be combined in the listed combinatorial syntheses which has not been derived from the application of molecular structural descriptors, validated as possessing a neighborhood property; and
(2) characterizing data, taking into account when necessary the structures of the cores with which the structural variations would be combined in the listed combinatorial syntheses, which has been derived from applying molecular structural descriptors, validated as possessing a neighborhood property, to the structural variation; and
d) associating with each core, data characterizing each core including:
(1) characterizing data which has not been derived from application of molecular structural descriptors, validated as possessing a neighborhood property; and
(2) characterizing data which is derived by the following additional steps:
(a) selecting a first core;
(b) selecting an attachment bond on the core;
(c) topomerically aligning the core;
(d) characterizing the core with CoMFA fields and the coordinates of the end points of the other attachment bonds;
(e) repeating steps (b) through (d) for all attachment bonds on the core;
(f) selecting a next core; and
(g) repeating steps (b) through (1′) for all cores
wherein the virtual library can be searched for product molecules having desired properties without the necessity of generating the product structures during the search.
3. A virtual library stored on computer readable medium of possible combinatorially derived product molecules generated by the following process:
a) defining chemical transformations and reagents and cores to be used to generate product molecules; and
b) using appropriate molecular descriptors to precalculate characteristics of the component parts of all possible product molecules
wherein the virtual library can be searched for product molecules having desired properties without the necessity of generating the product structures during the search.
4. A virtual library stored on computer readable medium of component parts of molecules and their characteristics generated by the following process:
a) defining chemical transformations and reagents and cores to be used to specify possible product molecules; and
b) using appropriate molecular descriptors, validated as possessing a neighborhood property, to precalculate characteristics of the component parts of all possible product molecules
wherein all possible product molecules combinatorially derived from the component parts can be searched for, without the necessity of generating the product structures during the search, for product molecules having desired properties by searching through only a combination of the descriptors of the component parts of the product molecules.
5. A virtual library stored on computer readable medium of structural variations, cores, and their associated molecular structural descriptors generated by the following process:
a) creating one or more files identifying one or more combinatorial reactions for one or more core structures;
b) creating separate structural variation files, associated with the reaction identifying files, in which are listed together the structural variations representative of those reactants which will react at each variation site of each combinatorial reaction;
c) associating with each structural variation, data, characterizing each structural variation including:
(1) characterizing data, which has not been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations, taking into account when necessary the structures of the cores with which the structural variations would be combined in the combinatorial syntheses; and
(2) characterizing data, which has been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations taking into account to the extent appropriate for application of the descriptor the structures of the cores with which the structural variation would be combined in the combinatorial syntheses
wherein the virtual library can be searched for product molecules derived from the combinatorial assembly of the structural variations and cores having desired properties, by combining descriptors of the structural variations and cores to generate descriptors representative of the product molecules, without the necessity of generating the product structures during the search.
6. A virtual library stored on computer readable medium of structural variations, cores, and their associated molecular structural descriptors generated by the following process:
a) creating one or more files identifying one or more combinatorial reactions for one or more core structures;
b) creating separate structural variation files, associated with the reaction identifying files, in which are listed together the structural variations representative of those reactants which will react at each variation site of each combinatorial reaction;
c) associating with each structural variation, data, characterizing each structural variation including:
(1) characterizing data, which has not been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations, taking into account when necessary the structures of the cores with which the structural variations would be combined in the combinatorial syntheses; and
(2) characterizing data, which has been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations taking into account to the extent appropriate for application of the descriptor the structures of the cores with which the structural variation would be combined in the combinatorial syntheses; and
d) associating with each core, data characterizing each core including:
(1) characterizing data which has not been derived from application of molecular descriptors, validated as possessing a neighborhood property; and
(2) characterizing data which is derived by the following additional steps:
(a) selecting a first core;
(b) selecting an attachment bond on the core;
(c) topomerically aligning the core;
(d) characterizing the core with CoMFA fields and the coordinates of the end points of the other attachment bonds;
(e) repeating steps (b) through (d) for all attachment bonds on the core;
(f) selecting a next core; and
(g) repeating steps (b) through (1′) for all cores
wherein the virtual library can be searched for product molecules derived from the combinatorial assembly of the structural variations and cores having desired properties, by combining descriptors of the structural variations and cores to generate descriptors representative of the product molecules, without the necessity of generating the product structures during the search.
7. A system for identifying from a virtual library stored on computer readable medium of structural variations, cores, and their associated molecular structural descriptors, product molecules derived from the combinatorial assembly of the structural variations and cores having desired properties, without the necessity of generating the product structures during the search, comprising:
a) a general purpose programmable digital computer further comprising:
(1) a central processing unit;
(2) random access memory;
(3) additional memory means for storing and accessing data; and
b) a virtual library stored in accessible memory of structural variations, cores, and their associated molecular structural descriptors, which can be searched for product molecules derived from the combinatorial assembly of the structural variations and cores having desired properties, by combining descriptors of the structural variations and cores to generate descriptors representative of the product molecules, without the necessity of generating the product structures during the search, generated by the following process:
(1) creating one or more files identifying one or more combinatorial reactions for one or more core structures;
(2) creating separate structural variation files, associated with the reaction identifying files, in which are listed together the structural variations representative of those reactants which will react at each variation site of each combinatorial reaction;
(3) associating with each structural variation, data, characterizing each structural variation including:
(a) characterizing data, which has not been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations, taking into account when necessary the structures of the cores with which the structural variations would be combined in the combinatorial syntheses; and
(b) characterizing data, which has been derived from applying at least one molecular structural descriptor, validated as possessing a neighborhood property, to the structural variations taking into account to the extent appropriate for application of the descriptor the structures of the cores with which the structural variation would be combined in the combinatorial syntheses.