Libraries of compounds having desired properties and methods for making and using them

Abstract

In alternative embodiments the invention provides libraries of compounds, or drugs or drug candidates, manufactured and selected for having a desired property such as a biological or a chemical activity, and methods for making and using them. In one embodiment, the invention provides methods for identifying desirable compounds from very large compound sets using a compound fragment as the query. In alternative embodiments, the invention provides methods of making compounds, and libraries of compounds, using a “feasible reaction” growth scheme.

What is claimed is: 
     
         1 . A method for making or identifying a plurality or a library of compounds having a desired property, such as a biological activity or a chemical property, or a method for making or identifying a drug or a lead compound having a desired property, such as a biological activity or chemical property, comprising:
 (1) (a) providing a chemistry space, or a plurality of synthesizable product molecules, or a plurality of synthetic compounds,   wherein the synthesizable product molecules are defined or described as a set of reactions, or a set of “feasible” reactions, with a set of reagent sets or starting materials associated with each reaction, and each reaction step of each reaction sequence is encoded separately so that intermediate structures are available as products in the chemistry space,   and optionally, the step (a) also comprises:
 (i) encoded separately for each reaction, a set of starting materials that produce products (compounds) that cannot be used in subsequent steps of the reaction scheme, 
 (ii) selecting reagent sets or starting materials associated with a particular reaction in a chemistry space, or a SYNTHEVERSE™ chemistry space, so that all or substantially all possible combinations define feasible reactions; 
 (iii) wherein the starting materials comprise carboxylic acids, carboxylic acid chlorides, primary amines, secondary amines, sulfonyl chlorides, alcohols, aldehydes, ketones, alkyl halides, aryl halides, boronic acids, trialkyl tin reagents, nitriles, isonitriles, imidates and the like as determined by the requirements of the reaction its elf; or, 
 (iv) wherein the reactions comprise: palladium mediated cross-coupling reactions such as the Suzuki, Negishi and Stille reactions, amine acylation, amine sulfonylation, nucleophilic displacement of an aromatic halogen, reduction, oxidation, alkylation of an amine, oxygen or carbon nucleophile, reductive amination, the Mitsonobu reaction, the Cadogan reaction, olefin metathesis, heterocyclic ring condensations, electrophilic aromatic substitution and the like; or 
 step (a) further comprises: steps (i) and (ii); steps (i) and (iii); steps (i) and (iv); steps (ii) and (iii); steps (ii) and (iv); steps (iii) and (iv); steps (i), (ii) and (iii); steps (ii), (iii) and (iv); steps (i), (iii) and (iv); and steps (i), (ii), (iii) and (iv); 
   (b) providing a fragment or a substructure of a fragment, and searching the starting material set of the chemistry space or a plurality of synthesizable product molecules of step (a) by (using) the fragment or substructure,   and optionally identifying a subset of starting materials that contain the fragment or fragment substructure,   wherein optionally the fragment or substructure of the fragment comprise a single ring or ring assembly or equivalent,   and optionally providing a set of simpler fragments (fragments of less complex structure) generated from an original (starting) structure, e.g., by stepwise removal of some or all atoms not contained in a ring or an equivalent structure,   and optionally the fragment (for example, in alternative embodiments, is a single ring or a ring assembly), is used to search the starting material by substructure, and a subset of starting materials is identified that contain the fragment or the fragment substructure,   and optionally a fragment comprises or consists of a single ring system that binds with only mM affinity to its target, and optionally the fragment has an ligand efficiency>0.5 kcal/mol/heavy atom,   and optionally the set of all possible combinations that contain at least one non-ring atom can be used to search the starting material set of the space by substructure to generate the starting material subset;   (c) generating product (compound) structures from the identified starting materials in step (b) in all reactions where they are used directly (in a one-step reaction scheme),   wherein optionally, because this is a one-step reaction scheme, the number of products per reaction is limited by the number of starting materials; and   (d) filtering the products (compounds) from step (c) to a manageable number (filtering the products from step (c) to a lesser number, or selecting a subset of the products (compounds) from step (c)) for a virtual screen or a synthesis and an assay or a combination thereof,   wherein optionally possible filters comprise: a reactive functional group removal, property limits, clustering and selection, random percent selection, or a combination thereof,   thereby making or identifying a plurality or a library of compounds, or a drug, having a desired property or a desired biological activity or chemical property; or   (2) a process or method as set forth in  FIG. 1 ,  FIG. 3 , or a process or method as set forth in  FIG. 1  and  FIG. 3 .   
     
     
         2 . The method of  claim 1 , wherein filtered products are further screened by a virtual or actual screening assay to identify products with (having) a desirable profile or a desirable property such as a biological activity or chemical property. 
     
     
         3 . The method of  claim 2 , wherein any product (compound) identified in step 1(d) or  claim 2 , is used in a query of step 1(b), wherein the reactions being searched contain the product (compound) as a starting material and new products (compounds) identified can be synthesized by a reaction scheme of two steps or more. 
     
     
         4 . The method of any of  claims 1  to  3 , wherein the process is applied again to any product of  claim 3 , and identifying a small subset of interest related to the initial fragment out of the entire chemistry space. 
     
     
         5 . The method of any of  claims 1  to  4 , wherein the process is repeated through  claim 4 , for all fragments and/or compounds of interest, or having a desired property or biological activity or chemical property, to provide or generate a set of compounds with the desirable profile (e.g., the desired biological property or activity or chemical property) derived from the original chemistry space,
 wherein optionally these products retain the design characteristics of the original chemistry space and are associated with a reaction scheme for their synthesis and the required starting materials. 
 
     
     
         6 . A method for making or identifying a plurality or a library of compounds having a desired property, such as a biological activity or chemical property, or a method for making or identifying a drug or a lead compound having a desired property, such as a biological activity or chemical property, comprising:
 (1) (a) providing a fragment or a substructure of a fragment (for example, in alternative embodiments, a single ring or ring assembly) for which a substructure search of the starting material set of the space described in  claim 1 , step (1)( a ), above returns no hits;   (b) determining the reactions where this fragment or substructure could react and is used directly;   (c) generating the product structures using the structure described in step (a) as the only representative of its reagent list and all the starting materials used for the other lists in each reaction identified in step (b),   and optionally, where this is a one-step reaction scheme and the fragment is not present in the original space, the number of products per reaction is limited by the number of starting materials of the other reactant types; and   (d) the products from step (c) are filtered to a manageable number for a virtual screen or synthesis and assay,   and optionally filters comprise reactive functional group removal, property limits, clustering and selection, random percent selection, or a combination thereof;   (2) the method of (1), further comprising: wherein the filtered products are then further screened by a virtual or actual screening assay to identify products with desirable profiles;   (3) the method of (1) or (2), wherein any product identified can then be used as a query for step (1)(a),   and optionally, the reactions being searched contain the product as a starting material and the new products identified can be synthesized by a reaction scheme of two steps or more,   and optionally, where the original starting material was not in the chemistry space, the generated products were also not present in the original chemistry space;   (4) the method of any of (1) to (3), wherein the process can be applied again to any product of step (3), identifying a small subset of interest related to the initial fragment that are an extension of the original chemistry space;   (5) the method of any of (1) to (4), further comprising: the process can be repeated for any fragment that contains functionality that can react in the reaction schemes described for the space, leading to a set of compounds with desirable profiles (e.g., a biological property or activity) (these products extend the design characteristics of the original space but are still associated with a reaction scheme for their synthesis and the required starting materials);   (6) the method of any of (1) to (5), further comprising: product structures are generated from the identified starting materials in all reactions where they are used in a primary intermediate (an intermediate made only from described starting materials)   and optionally, where this is a two-step reaction scheme, the number of intermediates per reaction is limited by the number of starting materials in the other reagent lists,   and optionally, the smallest number of products that contains each of the possible starting materials is generated,   optionally, if the two-step reaction scheme is:
     A+B →Intermediate  C  
 
     C+D →product  E  
 
   and there are 5 A starting materials, 10 B starting materials and 24 D starting materials, then the total number of products E is 5×10×24=1200,   optionally, if A 3  is the starting material of interest, then there are 240 possible E containing all the combinations of B and D, and optionally if intermediate C is enumerated 24 times to give A 3 B 1 , A 3 B 2  . . . A 3 B 10 , A 3 B 1 , . . . A 3 B 10 , A 3 B 1 , . . . A 3 B 4 , C is then combined with each individual D to generate 24 E: A 3 B 1 D 1 , A 3 B 2 D 2 , . . . A 3 B 10 D 10 , A 3 B 1 D 11 , . . . A 3 B 10 D 20 , A 3 B 1 D 21 , . . . A 3 B 4 D 24  . . . .   
     
     
         7 . A method for making or identifying a plurality or a library of compounds having a desired property, such as a biological activity or chemical property, or a method for making or identifying a drug or a lead compound having a desired property, such as a biological activity or chemical property, comprising:
 (a) providing a fragment or a substructure of a fragment for which a set of related compounds is desired by comparison to a calculated property or properties,   and optionally, the fragment or a substructure comprises a single ring or ring assembly;   (b) determining the desired range of each property relative to the value calculated for the initial query,   optionally each calculated property consists of a molecular weight, a ring count, a AlogP or another property that can be calculated on a per fragment or per atom basis,   optionally the desired range of each property comprises a lower or higher molecular weight, a lower or higher ring count, a lower or higher AlogP, or equivalents,   and optionally the desired range of each calculated property may not contain the value calculated for the initial query;   (c) generating all product structures that match the calculated property ranges;   wherein optionally:   (i) for each library, the properties are corrected for the changes produce by each reaction so that the properties measured are based on the product to be generated (because this query has no structural component, the number of products depends on the size range of the desired properties),   (ii) the number of products that will be generated can be determined before enumeration and the ranges adjusted until a manageable number can be produced;   (iii) the product structures from step (c) are filtered to a manageable number for a virtual screen or synthesis and assay, and optionally the filters comprise: a reactive functional group removal, property limits, clustering and selection, or random percent selection, or a combination thereof; and   (iv) further screening the filtered product structures by a virtual screen or actual screening assay for purchased or synthesized compounds to identify products with desirable profiles;   (v) the product structure identified in step (iii) or step (iv) is used as a query for step (b), and optionally, the properties ranges used are for the product of the previous steps, and optionally the process can be applied again to any product so identified,   (vi) identifying a small subset of interest with properties related to the initial fragment out of the entire chemistry space;   (vii) repeating step (b) and any one of, or subset of, or all of steps (i) to (vi), for all fragments of interest, leading to a set of compounds with desirable profiles (optionally a biological or a chemical property or activity) derived from the original chemistry space, wherein the products retain the design characteristics of the original space and are associated with a reaction scheme for their synthesis and the required starting materials.   
     
     
         8 . A computer-implemented method comprising the methods of any of  claims 1  to  7 , or a subset of any of the methods of  claims 1  to  7 . 
     
     
         9 . A computer program product, or a non-transitory computer program product, for implementing the methods of any of  claims 1  to  7 , or a subset of any of the methods of  claims 1  to  7 . 
     
     
         10 . A computer program product, or a non-transitory computer program product, for processing data, the computer program product comprising:
 a computer-executable logic contained on a computer-readable medium configured for causing the following computer-executed step to occur:   the computer-implemented method of  claim 8 ; or, the computer program product, or the non-transitory computer program product, of  claim 9 .   
     
     
         11 . The computer program product, or a non-transitory computer program product, of  claim 9  or  10 , wherein the computer-executable logic is further configured to cause the following steps to occur: receiving data elements or structures; and storing the data elements or structures in a memory, and optionally transmitting the identified structures, or plurality or library of compounds having the desired property. 
     
     
         12 . A Graphical User Interface (GUI) computer program product, or non-transitory computer program product, comprising a representation of the compounds and/or fragments used or identified in a method of any of  claims 1  to  7 , or the plurality or library of compounds having a desired property as made or identified in a method of any of  claims 1  to  7 . 
     
     
         13 . A computer system comprising a processor and a data storage device, wherein said data storage device has stored thereon: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; or, (d) a combination thereof. 
     
     
         14 . A non-transitory memory medium comprising program instructions for running, processing and/or implementing: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; or, (d) a computer system of  claim 13 ; or (e) a combination thereof. 
     
     
         15 . A computer-readable storage medium comprising a set of or a plurality of computer-readable instructions that, when executed by a processor of a computing device, cause the computing device to run, process and/or implement: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; (d) a computer system of  claim 13 ; (e) a non-transitory memory medium of  claim 14 ; or, (f) a combination thereof. 
     
     
         16 . A computer program storage device, embodied on a tangible computer readable medium, comprising: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; (d) a computer system of  claim 13 ; (e) a non-transitory memory medium of  claim 14 ; (f) a computer-readable storage medium of  claim 15 ; or (g) a combination thereof. 
     
     
         17 . A computer or equivalent electronic system, comprising: a memory; and a processor operatively coupled to the memory, the processor adapted to execute program code stored in the memory to: run, process and/or implement: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; (d) a computer system of  claim 13 ; (e) a non-transitory memory medium of  claim 14 ; (f) a computer-readable storage medium of  claim 15 ; (g) a computer program storage device of  claim 16 ; or, (e) a combination thereof. 
     
     
         18 . A system, comprising: a memory configured to: store structures or values associated with a plurality of structures or data points and/or a plurality of structures or data elements, and a processor adapted to execute program code stored in the memory to: run, process and/or implement: (a) a computer program product, or the non-transitory computer program product, for implementing a computer-implemented method of  claim 8 ; (b) a computer program product, or a non-transitory computer program product, of any of  claims 9  to  10 ; (c) a Graphical User Interface (GUI) computer program product, or non-transitory computer program product, of  claim 12 ; (d) a computer system of  claim 13 ; (e) a non-transitory memory medium of  claim 14 ; (f) a computer-readable storage medium of  claim 15 ; (g) a computer program storage device of  claim 16 ; (h) a system of  claim 17 ; or, (i) a combination thereof. 
     
     
         19 . A compound or a library of compounds made by a method of any of  claims 1  to  7 , wherein optionally the compounds comprise compounds having a biological or a chemical activity or property.