Generation of virtual combinatorial libraries of compounds

Details Generation of virtual combinatorial libraries of compounds Generation of virtual combinatorial libraries of compounds

1998-05-12

2001-06-26

Teska, Kevin J. (Department: 2123)

Data processing: structural design, modeling, simulation, and em

Simulating nonelectrical device or system

Chemical

C703S001000, C703S005000, C702S022000, C702S027000, C702S030000, C702S032000

Reexamination Certificate

active

06253168

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods for the generation of virtual combinatorial libraries of small molecules and other ligands. The members or molecules of the combinatorial libraries are generated in silico, and are designed to bind to identified target molecules in silico. The present invention also includes methods for docking the library members to desired target molecules whereby the library members are bound to such targets in silico.
BACKGROUND OF THE INVENTION
Combinatorial chemistry is a recent addition to the toolbox of chemists and represents a field of chemistry dealing with the synthesis of a large number of chemical entities. This is generally achieved by condensing a small number of reagents together in all combinations defined by a given reaction sequence. Advances in this area of chemistry include the use of chemical software tools and advanced computer hardware which has made it possible to consider possibilities for synthesis in orders of magnitude greater than the actual synthesis of the library compounds. The concept of “virtual library” is used to indicate a collection of candidate structures that would theoretically result from a combinatorial synthesis involving reactions of interest and reagents to effect those reactions. It is from this virtual library that compounds are selected to be actually synthesized.
Project Library (MDL Information Systems, Inc., San Leandro, Calif.) is said to be a desktop software system which supports combinatorial research efforts. (
Practical Guide to Combinatorial Chemistry,
A. W. Czaniik and S. H. DeWitt, eds., 1997, ACS, Washington, D.C.) The software is said to include an information-management module for the representation and search of building blocks, individual molecules, complete combinatorial libraries, and mixtures of molecules, and other modules for computational support for tracking mixture and discrete-compound libraries.
Molecular Diversity Manager (Tripos, Inc., St. Louis, Mo.) is said to be a suite of software modules for the creation, selection, and management of compound libraries. (
Practical Guide to Combinatorial Chemistry,
A. W. Czarnik and S. H. DeWitt, eds., 1997, ACS, Washington, D.C.) The LEGION and SELECTOR modules are said to be useful in creating libraries and characterizing molecules in terms of both 2-dimensional and 3-dimensional structural fingerprints, substituent parameters, topological indices, and physicochemical parameters.
Afferent Systems (San Francisco, Calif.) is said to offer combinatorial library software that creates virtual molecules for a database. It is said to do this by virtually reacting precursor molecules and selecting those that could be actually synthesized (Wilson,
C
&
EN,
Apr. 27, 1998, p.32).
While only Project Library and Molecular Diversity Manager are available commercially, these products do not provide facilities to efficiently track reagents and synthesis conditions employed for the introduction of fragments into the desired compounds being generated. Further, these products are unable to track mixtures of compounds that are generated by the introduction of multiple fragments by the use of multiple reagents. Therefore, it is desirable to have available methods for handling mixtures of compounds, as well as methods for the tracking of chemical reactions or transformations utilized in the synthesis of individual compounds and mixtures thereof.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided methods for the generation of virtual combinatorial libraries of small molecules. These library molecules or members are generated in silico. Library members of larger molecular weight, such as those that are polymeric in nature, may also be generated using the methods of the present invention.
The present invention further provides methods for tracking and maintaining in databases, the fragments, reagents and unique combinations of these used for the in silico generation of the library members. Methods for interfacing the information necessary for the generation of libraries in silicon as instructions designed to direct the actual synthesis of the library members on an instrument such as a parallel array synthesizer, are also provided in the present invention.
The present invention also provides methods for the in silico docking of the library members to identified target molecules. According to these methods, individual library members are allowed to bind to the desired target molecule in order to identify those library members that demonstrate high affinity binding to the targets.
While there are a number of ways to identify molecular interaction sites, identify compounds likely to interact with molecular interaction sites of RNA and other biological molecules, synthesize such compounds and analyze their binding, preferred methodologies are described in U.S. patent applications filed on even date herewith and assigned to the assignee of this invention. These application bear U.S. Ser. Nos. 09/076,440, 09/076,447, 09/076,206, 09/076,214 and 09/076,404, each of which was filed May 12, 1998. All of the foregoing applications are incorporated by reference herein in their entirety.


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