System and method of automatically generating chemical compounds with desired properties

• US 5,574,656 A
• Filed: 09/28/1995
• Issued: 11/12/1996
• 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): Trammell, James P.
• Assistant Examiner(s): Choi, Kyle J.
• Application Number:
  US08/535,822
• Time in Patent Office: 411 Days
• Field of Search: 364/496, 364/497, 364/500, 364/499, 436/43, 436/50, 436/55, 423/659, 424/2, 935/85-88
• 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 system for generating compounds having a prescribed set of activity/properties, comprising:

one or more chemical synthesis robots to robotically synthesize, in accordance with robotic synthesis instructions, a directed diversity chemical library comprising a plurality of chemical compounds;

one or more analysis robots to robotically analyze said chemical compounds to obtain structure-activity data pertaining thereto, said analysis robots including at least one of an assay module, a chemical synthesis indicia generator, a structure and composition analysis module, a physical and electronic property analysis module, and a three dimensional receptor mapping module;

a synthesis protocol generator, comprising;

comparing means for comparing said structure-activity data of said chemical compounds against said prescribed set of activity/properties to identify any of said chemical compounds substantially conforming to said prescribed set of activity/properties;

classifying means for classifying said identified chemical compounds as lead compounds;

structure-activity model derivation means for analyzing said structure-activity data of said compounds and historical structure-activity data pertaining to compounds synthesized and analyzed in the past to derive structure-activity models having enhanced predictive and discriminating capabilities;

reagent identifying means for identifying, in accordance with said structure-activity models, reagents from a reagent database that, when combined, will produce a set of compounds predicted to exhibit activity/properties more closely matching said prescribed set of activity/properties; and

robotic synthesis instruction generating means for generating robotic synthesis instructions that, when executed, enable said chemical synthesis robots to robotically synthesize said set of compounds.

2. A computer program product comprising a computer useable medium having computer program logic recorded thereon for enabling a processor in a system to assist in generating compounds having a prescribed set of activity/properties, said system comprising a chemical synthesizer to synthesize, in accordance with synthesis instructions, a directed diversity chemical library comprising a plurality of chemical compounds, and an analyzer to analyze said chemical compounds to obtain structure-activity data pertaining thereto, said computer program logic comprising:

structure-activity model derivation means for enabling the processor to analyze said structure-activity data of said compounds and historical structure-activity data pertaining to compounds synthesized and analyzed in the past to derive structure-activity models having enhanced predictive and discriminating capabilities;

reagent identifying means for enabling the processor to identify, in accordance with said structure-activity models, reagents from a reagent database that, when combined, will produce a set of compounds predicted to exhibit activity/properties more closely matching said prescribed set of activity/properties; and

synthesis instruction generating means for enabling the processor to generate synthesis instructions that, when executed, enable said chemical synthesizer to synthesize said set of compounds.