System, method, and computer program product for at least partially automatically generating chemical compounds with desired properties from a list of potential chemical compounds to synthesize

• US 5,901,069 A
• Filed: 08/01/1997
• Issued: 05/04/1999
• Est. Priority Date: 09/16/1994
• Status: Expired due to Term

• Current Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Soll, Richard M., Bone, Roger F., Salemme, Francis R., Agrafiotis, Dimitris K.
• Primary Examiner(s): KEMPER, MELANIE A
• Application Number:
  US08/904,737
• Time in Patent Office: 641 Days
• Field of Search: 364/500, 364/496, 364/497, 364/499, 364/578, 364/528.03, 436/43, 436/50, 436/55, 423/659, 424/2, 935/85-88, 422/187, 702/27, 702/31
• US Class Current: 506/5
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00592 Split-and-pool, mix-and-divide processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00599 Solution-phase processes
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00698 Measurement and control of process parameters
• CPC Class Codes: B01J 2219/007 Simulation or vitual synthesis
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: C07K 1/047 Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 50/08 Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
• CPC Class Codes: G16B 15/30 Drug targeting using structural data; Docking or binding prediction
• CPC Class Codes: G16B 35/00 ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
• CPC Class Codes: G16C 20/10 Analysis or design of chemical reactions, syntheses or processes
• CPC Class Codes: G16C 20/30 Prediction of properties of chemical compounds, compositions or mixtures
• CPC Class Codes: G16C 20/60 : In silico combinatorial chemistry
• CPC Class Codes: G16C 20/62 : Design of libraries
• CPC Class Codes: G16C 20/70 : Machine learning, data mining or chemometrics
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis

Abstract

A computer based, iterative process for generating chemical entities with defined physical chemical and/or bioactive properties. During each iteration of the process, (1) a directed diversity chemical library is robotically generated in accordance with robotic synthesis instructions; (2) the compounds in the directed diversity chemical library are analyzed to identify compounds with the desired properties; (3) structure-property data are used to select compounds to be synthesized in the next iteration; and (4) new robotic synthesis instructions are automatically generated to control the synthesis of the directed diversity chemical library for the next iteration.

Claims

1. A computer based synthesis protocol generator for use in a system that generates compounds having a prescribed set of activities/properties, said synthesis protocol generator comprising:

means for generating a list of potential chemical compounds, each of said potential chemical compounds comprising one or more reagents from a reagent list, said reagent list comprising a list of reagents that, as selectively combined, will produce a set of compounds that will exhibit activities/properties more closely matching said prescribed set of activities/properties as predicted by structure-activity models derived from analysis of (a) structure-activity data of compounds contained in a directed diversity chemical library, and (b) historical structure-activity data of compounds synthesized and analyzed in the past;

candidate compound identifying means for identifying from said list of potential chemical compounds a plurality of candidate compounds suitable for synthesis; and

synthesis instruction generating means and executing means for generating and executing synthesis instructions that control the synthesis of at least a subset of said candidate compounds.

2. The synthesis protocol generator of claim 1, further comprising:

optimal set selecting means for selecting an optimal set of said candidate compounds to synthesize based on at least one of the following factors;

(i) their respective predicted abilities to exhibit activity/properties more closely matching said prescribed set of activity/properties as indicated by said structure-activity models;

(ii) their respective predicted abilities to validate said structure-activity models;

(iii) their respective predicted abilities to discriminate between said structure-activity models;

(iv) their respective predicted abilities to have superior three-dimensional receptor fit; and

(v) similarity between their respective structural, physical, or chemical characteristics and characteristics of compounds in a structure-activity database whose activity/properties most closely conform to said prescribed set of activity/properties.

3. The synthesis protocol generator of claim 2, wherein said optimal set selecting means comprises:

means for selecting said optimal set by individually ranking said candidate compounds based on at least one of factors (i)-(v).

4. The synthesis protocol generator of claim 2, wherein said optimal set selecting means comprises:

means for selecting said optimal set by ranking combinations of said candidate compounds based on at least one of factors (i)-(v).

5. The synthesis protocol generator of claim 1, further comprising:

structure-activity model derivation means for analyzing structure-activity data of said compounds contained in said directed diversity chemical library and said historical structure-activity data pertaining to said compounds synthesized and analyzed in the past to derive said structure-activity models, wherein said structure-activity models have enhanced predictive and discriminating capabilities.

6. The synthesis protocol generator of claim 1, further comprising:

reagent identifying means for identifying, in accordance with said structure-activity models, reagents from a reagent database for inclusion in said reagent list.

7. A computer based method of generating compounds having a prescribed set of activities/properties, the method comprising the steps of:

(1) generating a list of potential chemical compounds, each of said potential chemical compounds comprising one or more reagents from a reagent list, said reagent list comprising a list of reagents that, as selectively combined, will produce a set of compounds that will exhibit activities/properties more closely matching said prescribed set of activities/properties as predicted by structure-activity models derived from analysis of (a) structure-activity data of compounds contained in a directed diversity chemical library, and (b) historical structure-activity data of compounds synthesized and analyzed in the past;

(2) identifying from said list of potential chemical compounds a plurality of candidate compounds suitable for synthesis;

(3) generating synthesis instructions that control the synthesis of at least a subset of said candidate compounds; and

(4) executing said synthesis instructions to thereby generate said at least a subset of said candidate compounds.

8. The computer based method of claim 7, further comprising the step of:

(4) selecting an optimal set of said candidate compounds to synthesize based on at least one of the following factors;

(i) their respective predicted abilities to exhibit activity/properties more closely matching said prescribed set of activity/properties as indicated by said structure-activity models;

(ii) their respective predicted abilities to validate said structure-activity models;

(iii) their respective predicted abilities to discriminate between said structure-activity models;

(iv) their respective predicted abilities to have superior three-dimensional receptor fit; and

(v) similarity between their respective structural, physical, or chemical characteristics and characteristics of compounds in a structure-activity database whose activity/properties most closely conform to said prescribed set of activity/properties.

9. The computer based method of claim 8, wherein step (4) comprises the step of:

selecting said optimal set by individually ranking said candidate compounds based on at least one of factors (i)-(v).

10. The computer based method of claim 8, wherein step (4) comprises the step of:

selecting said optimal set by ranking combinations of said candidate compounds based on at least one of factors (i)-(v).

11. The computer based method of claim 7, further comprising the step of:

analyzing structure-activity data of said compounds contained in said directed diversity chemical library and said historical structure-activity data pertaining to said compounds synthesized and analyzed in the past to derive said structure-activity models, wherein said structure-activity models have enhanced predictive and discriminating capabilities.

12. The computer based method of claim 7, further comprising the step of:

identifying, in accordance with said structure-activity models, reagents from a reagent database for inclusion in said reagent list.

13. A computer program product comprising a computer useable medium having computer program logic recorded thereon for enabling a processor to assist in generating compounds having a prescribed set of activities/properties, said computer program logic comprising:

means for enabling a computer to assist in generating a list of potential chemical compounds, each of said potential chemical compounds comprising one or more reagents from a reagent list, said reagent list comprising a list of reagents that, as selectively combined, will produce a set of compounds that will exhibit activities/properties more closely matching said prescribed set of activities/properties as predicted by structure-activity models derived from analysis of (a) structure-activity data of compounds contained in a directed diversity chemical library, and (b) historical structure-activity data of compounds synthesized in the past;

candidate compound identifying means for enabling a computer to assist in identifying from said list of potential chemical compounds a plurality of candidate compounds suitable for synthesis; and

synthesis instruction generating means for enabling a computer to assist in generating synthesis instructions that control synthesis of at least a subset of said candidate compounds.

14. The computer program product of claim 13, wherein said computer program logic further comprises:

optimal set selecting means for enabling a computer to at least assist in selecting an optimal set of said candidate compounds to synthesize based on at least one of the following factors;

(i) their respective predicted abilities to exhibit activity/properties more closely matching said prescribed set of activity/properties as indicated by said structure-activity models;

(ii) their respective predicted abilities to validate said structure-activity models;

(iii) their respective predicted abilities to discriminate between said structure-activity models;

(iv) their respective predicted abilities to have superior three-dimensional receptor fit; and

(v) similarity between their respective structural, physical, or chemical characteristics and characteristics of compounds in a structure-activity database whose activity/properties most closely conform to said prescribed set of activity/properties.

15. The computer program product of claim 14, wherein said optimal set selecting means comprises:

means for enabling a computer to at least assist in selecting said optimal set by individually ranking said candidate compounds based on at least one of factors (i)-(v).

16. The computer program product of claim 14, wherein said optimal set selecting means comprises:

means for enabling a computer to at least assist in selecting said optimal set by ranking combinations of said candidate compounds based on at least one of factors (i)-(v).

17. The computer program product of claim 13, wherein said computer program logic further comprises:

structure-activity model derivation means for enabling a computer to at least assist in analyzing structure-activity data of said compounds contained in said directed diversity chemical library and said historical structure-activity data pertaining to said compounds synthesized and analyzed in the past to derive said structure-activity models, wherein said structure-activity models have enhanced predictive and discriminating capabilities.

18. The computer program product of claim 13, wherein said computer program logic further comprises:

reagent identifying means for enabling a computer to at least assist in identifying, in accordance with said structure-activity models, reagents from a reagent database for inclusion in said reagent list.