Source: http://www.google.com/patents/US6678619?dq=alibre+inassignee:alibre
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Patent US6678619 - Method, system, and computer program product for encoding and building ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe present invention provides a method, system, and computer program product for encoding and building products of a virtual combinatorial library. A chemical reaction and reagent data for forming products of the virtual combinatorial library are encoded in a computer readable form. A compiler then...http://www.google.com/patents/US6678619?utm_source=gb-gplus-sharePatent US6678619 - Method, system, and computer program product for encoding and building products of a virtual combinatorial libraryAdvanced Patent SearchPublication numberUS6678619 B2Publication typeGrantApplication numberUS 09/956,252Publication dateJan 13, 2004Filing dateSep 20, 2001Priority dateSep 20, 2000Fee statusPaidAlso published asUS20020045991, WO2002025504A2, WO2002025504A3Publication number09956252, 956252, US 6678619 B2, US 6678619B2, US-B2-6678619, US6678619 B2, US6678619B2InventorsVictor S. Lobanov, Dimitris K. Agrafiotis, Francis R. SalemmeOriginal AssigneeVictor S. Lobanov, Dimitris K. Agrafiotis, Francis R. SalemmeExport CitationBiBTeX, EndNote, RefManPatent Citations (15), Non-Patent Citations (187), Referenced by (10), Classifications (21), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetMethod, system, and computer program product for encoding and building products of a virtual combinatorial library
US 6678619 B2Abstract
The present invention provides a method, system, and computer program product for encoding and building products of a virtual combinatorial library. A chemical reaction and reagent data for forming products of the virtual combinatorial library are encoded in a computer readable form. A compiler then operates on the encoded information and generates reagent mapping data. The compiler compiles the encoded chemical reaction to genenerate computer instructions that control the operation of a processor. A compact data structure containing data is generated and stored in a memory. This data structure is then used to gain immediate access to any of the products of the virtual combinatorial library.
This application claims the benefit of U.S. Provisional Application No. 60/234,206, filed Sep. 20, 2000, which is incorporated by reference herein in its entirety.
The present invention relates to combinatorial chemistry. More particularly, it relates to virtual combinatorial libraries used in computer aided molecular design.
Among the tools available to a medicinal chemist, combinatorial chemistry is one of the most powerful and best suited for exploring chemical space in search of new drug leads. Combinatorial chemistry provides access to millions of novel compounds from a limited number of building blocks using synthetic procedures that work reliably across a wide range of starting materials.
Experience suggests that selections based exclusively on molecular diversity tend to include “extreme” reagents, which can increase cost, cause delays due to limited availability, lead to unforeseen synthetic problems, and produce unusual compounds of limited pharmaceutical interest. The hit rate achieved with such libraries has proven disappointingly low (see A. R. Leach and M. M. Hann, The in silico world of virtual libraries, Drug Discovery Today, 2000, 5, 326-336, each of which is incorporated by reference herein in its entirety), and the compounds often exhibit unfavorable biological properties that could potentially result in ADME liabilities (see C. A. Lipinski et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23, 3-25; and D. N. Rassokhin and D. K. Agrafiotis, Kolmogorov-Smirnov statistic and its application in library design, J. Mol. Graphics Modell., 2000, 18(4-5), 370-384, each of which is incorporated by reference herein in its entirety). Thus, the focus in the design of probe libraries has began to shift from pure diversity to chemical feasibility, availability of monomers, and drug likeness (see D. N. Rassokhin and D. K. Agrafiotis, Kolmogorov-Smirnov statistic and its application in library design, J. Mol. Graphics Modell., 2000, 18(4-5), 370-384; A. R. Leach and M. M. Hann, The in silico world of virtual libraries, Drug Discovery Today, 2000, 5, 326-336; J. Sadowski and H. Kubinyi, A scoring scheme for distinguishing between drugs and non-drugs. J. Med. Chem., 1998, 41, 3325-3329; Ajay et al., Can we learn to distinguish between “drug-like” and “nondrug-like” molecules?, J. Med. Chem., 1998, 41, 3314-3324; and J. Wang and K. Ramnarayan, Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds, J. Comb. Chem., 1999, 1, 524-533, each of which is incorporated by reference herein in its entirety).
FIG. 1 illustrates a flowchart of an embodiment 100 for encoding the products of a virtual combinatorial library in a compact data structure or library object 180 according to the invention. As described herein, embodiment 100 facilitates fast, “on-demand” enumeration or building of combinatorial products. As described in detail below, method 100 comprises three operation stages or steps. A person skilled in the relevant art will understand how to implement embodiment 100 based on the description of the invention herein.
As noted above, further features of embodiment 100 are described elsewhere herein. As will be understood by a person skilled in the relevant art given the description herein, library object 180 can be used to build products (e.g., generate product connection data) of a virtual combinatorial library “on-demand.”
In an embodiment, an RSL is designed as an extension of the Tool Command Language (Tcl) (see J. Ousterhout, Tcl and the Tk Toolkit, Addison-Wesley, ISBN 0-201-63337-X, 1994, which is incorporated by reference herein in its entirety), which has a fairly simple and human-readable syntax. Each combinatorial reaction is defined as a named Tcl procedure, thus providing a framework for creating libraries of common reaction schemes. RSL procedures are designed to be compilable into a sequence of parameterized function calls that are be executed in order to assemble the product structures. This facilitates fast, “on-demand” enumeration of combinatorial products.
Sometimes it is difficult, if not impossible, to write a single SMARTS string that will match only the reactive substructure pattern. In this case, one can specify the substructures that are not reactive. For example, a simple amine pattern “C[NH2]” will match an amide as well, which is not susceptible to reductive amination. One can either modify the amine pattern as “[CX4][NH2]” or define the amide substructure “C(═O)[NH2]” and designate it as non-reactive. When non-reactive patterns are present, the invention looks for an overlap between the matched reactive and non-reactive substructures, and if they have at least one atom in common the reactive structure will be invalidated.
In an embodiment, after the reacting substructures of the reagents are defined, the remaining code of the reaction script encodes the instructions for product assembly. Once the product is defined (line 5 in FIG. 8), its name becomes a Tcl command that supports a series of molecular operations. These operations include addition of previously defined reagents, removal of atoms, addition and removal of bonds, changing of the bond order, etc. A list of the most frequently used operators for an embodiment is given in FIG. 9. Note that with the exception of the “add” command, which instructs the program to add the connection table of the reagent to the connection table of the product, the remaining assembly instructions require specification of individual atoms affected by the instructions. Individual atoms participating in the chemical transformation are referred to by the respective reagent's name and by the zero-based indices of the matching atoms in the respective SMARTS pattern. For example, the nitrogen atom from an “amine” reagent defined with the SMARTS pattern “C[NH2]” is referred to as “amine:1”. Since SMARTS strings are written in a single line, all atom specifications defined in a pattern can be unambiguously numbered from left to right as they appear in the pattern string. Note that hydrogen atoms are part of the atom specification in SMARTS and therefore cannot be individually addressed. (See FIG. 9.)
Since the reagent definition can include multiple SMARTS patterns, it is important that the atoms referenced in the assembly instructions have the same indices in every pattern. For instance, the nitrogen atom in both the primary and secondary amines should have the same index (e.g. 1) if a single assembly instruction is to apply to both of them. Fortunately, it is always possible to write SMARTS specifications in the desired order using “ring closures” (numbers), disconnections (dots) and recursive atom environments. Moreover, in most cases, SMARTS encoding lends itself naturally to this requirement since multiple patterns are typically used to define variations of the same functionality, such as primary and secondary amines.
In embodiments of the invention, most if not all of the assembly instructions are obvious (e.g., “insert bond,” “remove atom,” “remove bond,” “set atom charge,” “set bond order,” etc.) Note that there is no instruction to insert a single atom since all the atoms of a product must come from the reagents in accordance with the mass preservation law. Special instructions are also provided to define the stereochemical outcome of reactions controlled by steric approach preferences. In RSL embodiment, the major product of a stereochemical reaction can be specified, for example, in two ways: (1) via the configuration of the nascent chiral center(s), and (2) via the stereochemical character of a bond during addition and elimination. FIGS. 10-17 illustrate some examples of stereochemistry encoding in an RSL embodiment.
The stereochemical configuration of a formed chiral center can be identified as “unspecified,” “racemic” or “inverse.” “Unspecified” indicates that the exact configuration of the products is unknown or irrelevant (default). “Racemic” indicates that both the R and S stereoisomers are formed in comparable quantities. “Inverse” exchanges one of the chiral center's substituents during the reaction and inverts its configuration. The R/S assignment of the chiral center is automatically determined based on the original configuration and the CIP priority of the new substituent. In general, the stereochemical configuration of an atom can be specified by listing its substituents in clockwise order and designating the last substituent as an up (in front of the plane) or a down (behind the plane) wedge. In this case, the R/S assignment is based on the CIP priorities and order of the substituents. Alternatively, the R/S configuration of the chiral center could be explicitly specified, but this option is rarely used since the label depends on the CIP priorities of the individual building blocks.
Stereochemical ambiguity also emerges when the reaction mechanism involves multiple centers. For example, dehydrohalogenation leads to double bond formation via an anti elimination pathway, whereby two substituents are removed from opposite sides of the reduced single bond. The resulting double bond can be cis or trans depending on the original configuration of the bonded atoms. In an embodiment, RSL defines two keywords, “syn_product” and “anti_product,” to specify whether an addition or elimination reaction proceeds in a syn or anti manner. Note that it is not always possible to identify a single product using these keywords. For completeness, the configuration of the double bond can also be explicitly specified as E or Z.
Finally, the “enumerate” statement triggers the creation of the virtual library. Although semantically simple, this statement is the complicated in its implementation. For scalability, the enumeration of the products must be implicit and must circumvent the creation of a connection table or even a record for every product in the library. This objective is accomplished by dividing the enumeration process in two steps. During the first step, the reacting and interfering functionalities are identified by matching the corresponding SMARTS patterns, and any reagents that are not compatible with the reaction transform are eliminated from further processing. This step involves mostly substructure searching, and scales linearly with the number of reagents that make up the virtual library. The second step involves the generation of products and is delayed until a particular product is requested. That is, the construction of the connection table of a particular product occurs only when its structure is needed for display or evaluation, and in many cases this never happens. In the next section, several methods to analyze a virtual library are described that require the enumeration of only a minor fraction of its members (products).
In order to accelerate the “on-demand” assembly of products, the mappings of the reactive groups matched by the SMARTS patterns are stored within the virtual library along with the compiled sequence of assembly operators. Thus, when the structure of a product is needed, no time is spent on substructure searching or parsing assembly instructions. This design and the speed of the underlying foundation classes and molecular perception algorithms upon which the invention software is based, enable the construction of products at a rate of 10,000 structures per second on a 800 MHz Pentium III processor, including full perception of valence, rings and aromaticity.
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A., "Fuzzy Sets", Information and Control, Academic Press Inc., vol. 8, No. 3, Jun. 1965, pp. 338-353.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS7702467Jun 29, 2005Apr 20, 2010Numerate, Inc.Molecular property modeling using rankingUS8725573 *May 11, 2005May 13, 2014Amazon Technologies, Inc.Method and system for creating and maintaining a virtual libraryUS8765484Jan 31, 2003Jul 1, 2014The Regents Of The University Of CaliforniaOptically encoded particlesUS9181634 *Dec 21, 2004Nov 10, 2015The Regents Of The University Of CaliforniaOptically encoded particles through porosity variationUS20030018598 *Jul 19, 2001Jan 23, 2003Cawse James NormanNeural network method and systemUS20030229477 *Feb 24, 2003Dec 11, 2003Libraria, Inc.Separation of matching and mapping in chemical reaction transformsUS20050042764 *Jan 31, 2003Feb 24, 2005Sailor Michael JOptically encoded particlesUS20050288868 *Jun 29, 2005Dec 29, 2005Duffy Nigel PMolecular property modeling using rankingUS20070148695 *Dec 21, 2004Jun 28, 2007Sailor Michael JOptically encoded particles, system and high-throughput screeningUS20100161531 *Mar 3, 2010Jun 24, 2010Numerate, Inc.Moleclar property modeling using ranking* Cited by examinerClassifications U.S. Classification506/13, 702/32, 506/24International ClassificationC40B50/02, B01J19/00, G06F19/00, G06F17/30, C07B61/00, C07K1/04Cooperative ClassificationB01J2219/0072, C07K1/047, C40B50/02, B01J19/0046, C40B40/00, B01J2219/007, B01J2219/00695, B01J2219/00689European ClassificationG06F19/70, B01J19/00C, C40B50/02, C07K1/04CLegal EventsDateCodeEventDescriptionJan 2, 2002ASAssignmentOwner name: 3-DIMENSIONAL PHARMACEUTICALS, INC, PENNSYLVANIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LOBANOV, VICTOR S.;AGRAFIOTIS, DIMITRIS K.;SALEMME, FRANCIS R.;REEL/FRAME:012427/0722;SIGNING DATES FROM 20011214 TO 20011218Aug 17, 2004CCCertificate of correctionJun 26, 2007FPAYFee paymentYear of fee payment: 4Jun 15, 2011FPAYFee paymentYear of fee payment: 8Jul 1, 2015FPAYFee paymentYear of fee payment: 12RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services