Source: http://www.google.com/patents/US6434490?dq=6825444
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Patent US6434490 - Method of generating chemical compounds having desired properties - Google Patents
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...http://www.google.com/patents/US6434490?utm_source=gb-gplus-sharePatent US6434490 - Method of generating chemical compounds having desired properties
Publication number US6434490 B1
Application number US 09/213,156
Also published as CA2199264A1, EP0781436A1, EP0781436A4, US5463564, US5574656, US5684711, US5901069, US20030033088, WO1996008781A1
Publication number 09213156, 213156, US 6434490 B1, US 6434490B1, US-B1-6434490, US6434490 B1, US6434490B1
Patent Citations (68), Non-Patent Citations (167), Referenced by (63), Classifications (41), Legal Events (4)
US 6434490 B1
1. A method for at least partially automatically generating compounds having at least a prescribed set of properties, comprising the steps of:
(1) robotically synthesizing a directed diversity chemical library comprising a plurality of chemical compounds;
(2) analyzing said chemical compounds to obtain structure-activity data pertaining thereto;
(3) comparing said structure-activity data of said chemical compounds against said prescribed set of properties to identify any of said chemical compounds conforming to said prescribed set of properties;
(4) classifying said identified chemical compounds as lead compounds;
(5) analyzing said structure-activity data of said lead compounds and historical structure-activity data pertaining to compounds synthesized and analyzed in the past to derive structure-activity models having predictive and discriminating capabilities;
(6) identifying, in accordance with said structure-activity models, reagents that, when combined, will produce a first set of compounds predicted to exhibit activity/properties more closely matching said prescribed set of properties;
(7) generating robotic synthesis instructions that, when performed, enable robotic synthesis of said first set of compounds; and
(8) robotically synthesizing a new directed diversity chemical library comprising a plurality of chemical compounds using said generated synthesis instructions and repeating steps (2) through (7).
identifying reagents that, when combined, will produce a second set of compounds predicted to have a superior ability to validate said structure-activity models, wherein said first and second sets of compounds are not mutually exclusive;
wherein step (7) comprises the step of generating synthesis instructions that, when performed, enable synthesis of said second set of compounds.
identifying reagents that, when combined, will produce a second set of compounds predicted to have a superior ability to discriminate between said structure-activity models, wherein said first and second sets of compounds are not mutually exclusive;
identifying reagents that, when combined, will produce a second set of compounds predicted to have a superior ability to validate said structure-activity models, and a third set of compounds predicted to have a superior ability to discriminate between said structure-activity models, wherein said first, second, and third sets of compounds are not mutually exclusive;
wherein step (7) comprises the step of generating synthesis instructions that, when performed, enable synthesis of said second and third set of compounds.
identifying reagents that, when combined, will produce a second set of compounds predicted to have superior three-dimensional receptor fit, wherein said first and second sets of compounds are not mutually exclusive;
Manufacturer City State Model
Advanced ChemTech Louisville KY 357 MPS
Rainin Woburn MA Symphony
Perkin-Elmer Corporation Applied Foster City CA 433A
Millipore Bedford MA 9050 Plus
Hewlett-Packard Company Palo Alto CA 5890
Varian Associates Palo Alto CA
Shimadzu Scientific Inst. Columbia MD GC-17A
Fisons Instruments Beverly MA GC 8000
Hewlett-Packard Company Palo Alto CA 1050, 1090
Varian Associates Inc. Palo Alto CA
Rainin Instrument Co. Woburn MA
Shimadzu Scientific Inst. Columbia MD LC-10A
Waters Chromatography Milford MA Millennium
Perkin-Elmer Corporation Norwalk CT
Hitachi Instruments Inc. San Jose CA
Hewlett-Packard Company Palo Alto CA
Kratos Analytical Inc. Ramsey NJ MS80RFAQ
Finnigan MAT San Jose CA Vision 2000,
Fisons Instruments Beverly MA API LC/MS,
Perkin-Elmer Sciex Norwalk CT API-III
The task in step 608 of selecting the optimal set of compounds for the next directed diversity chemical library involves a search over the entire set of subsets of the candidate compounds (identified during step 606), wherein each subset has k members, where k may vary from one subset to the next and is preferably within the following range: 1000≦k≦5000. Given a list of n compounds produced during step 606, the present invention in step 608 identifies which subset of k compounds best satisfies requirements (1), (2) and (3) outlined above. The number of distinct k-subsets of an n-set S is given by EQ. 1: N = ∑ k = k 1 k 2  n ! k !   ( n - k ) ! EQ .  1
where k1 and k2 represent the minimum and maximum number of members in a subset, respectively. As indicated above, k1 is preferably equal to 1000 and k2 is preferably equal to 5000. This task is combinatorially explosive, i.e., in all but the simplest cases, N is far too large to allow for the construction and evaluation of each individual subset given current data processing technology. As a result, a variety of stochastic modeling techniques can be employed, which are capable of providing good approximate solutions to combinatorial problems in realistic time frames. However, the present invention envisions and includes the construction and evaluation of each individual subset once computer technology advances to an appropriate point.
EXAMPLE Generation of Lead Thrombin Inhibitor
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EP0355628A1 Aug 11, 1989 Feb 28, 1990 Siemens Aktiengesellschaft Process for chemically decontaminating the surface of a metallic construction element of a nuclear power plant
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U.S. Classification 702/27, 435/7.24, 435/69.1, 435/91.2
International Classification A61K38/55, C40B30/02, A61P7/02, G06F19/00, C40B50/08, G06F17/50, B01J19/00, C40B40/10, C07B61/00, C07K1/04, C40B50/02
Cooperative Classification Y10T436/11, C40B50/02, B01J19/0046, B01J2219/00691, C40B30/02, C07K1/047, G06F19/704, B01J2219/0059, B01J2219/007, B01J2219/00599, C40B40/10, B01J2219/00695, B01J2219/00596, G06F19/702, B01J2219/00698, B01J2219/00725, C40B50/08, B01J2219/0072, B01J2219/00592, B01J2219/00689, G06F19/707
European Classification C40B30/02, G06F19/70, C07K1/04C, B01J19/00C, C40B50/02