Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
1999-04-23
2002-01-29
Horlick, Kenneth R. (Department: 1656)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
C702S027000, C706S045000, C706S047000
Reexamination Certificate
active
06343257
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for constructing virtual libraries of molecules and screening these libraries for the existence of a predefined structural motif, and in particular identifying molecules which meet the constraints imposed by a pharmacophore.
BACKGROUND OF THE INVENTION
A classical approach to the problem of drug-lead optimization—the so-called “lead explosion” method—involves making large numbers of slightly modified analogs of the drug lead compound. Yet while in some cases this can result in analogs with largely increased binding affinities to the desired target, the major drawback of this method is that it results in a set of highly similar molecules. Thus, if the original lead compound fails at a later stage of the drug development process, for reasons which are not directly related to its target binding capabilities, such as problems of solubility, toxicity, or bioavailability for example, there is a good chance that the majority of the second generation analogs will fail likewise.
A more recent approach that overcomes this drawback involves identifying from a set of lead compounds an “active structural motif”—in particular but not limited to a pharmacophore—and searching, by computer algorithms, a database of compounds for its existence. The result of this search may be a set of diverse molecules that display the predefined structural motif [Y. C. Martin, 3D Database Searching in Drug Design,
J. Med. Chem.
35, 2145(1992); A. C. Good and J. S. Mason, Three Dimensional Structure Database Searches,
Reviews in Comp. Chem.
7, 67(1996)].
The pharmacophore has proven to be a highly valuable and useful concept in drug discovery and drug-lead optimization. A pharmacophore is defined as a distinct three dimensional (3D) arrangement of chemical groups essential for biological activity. Since a pharmaceutically active molecule must interact with one or more molecular structures within the body of the subject in order to be effective, and the desired functional properties of the molecule are derived from these interactions, each active compound must contain a distinct arrangement of chemical groups which enable this interaction to occur. The chemical groups, commonly termed descriptor centers, can be represented by (a) an atom or group of atoms; (b) pseudo-atoms, for example a center of a ring, or the center of mass of a molecule; (c) vectors, for example atomic pairs, electron lone pair directions, or the normal to a plane. Clearly, the ability to design, or identify from large databases, pharmaceutically useful molecules according to the pharmacophore would be highly effective both in the process of drug discovery and in the process of drug lead optimization.
The pharmacophore can be constructed either directly or indirectly. In the direct method and pharmacophore descriptor centers are inferred from studying the X-ray or NMR structure of a receptor-ligand complex, or by a shape-complementarity function analysis of the receptor binding site. In the indirect method the structure of the receptor is unknown and therefore the pharmacophore descriptor centers are inferred by overlaying the 3-dimensional conformations of active compounds and finding the common, overlapping functional groups.
The virtually screened databases may be commercially and/or publicly available or corporate databases of existing compounds, or virtual, existing solely on the computer. In both cases the size of the lists is commonly on the order of tens to hundreds of thousands of molecules. This size limitation, in particular for the virtual databases, commonly stems from limitations of disk space needed to store the library and the speed of the algorithms that are available to scan it.
Yet databases in the above size range comprise only a small subset of chemical space. For example, a database of 100 peptidomimetic scaffolds with 6 side-chain attachment points for the 18 (non-glycine or proline) natural amino acid sidechains can potentially combine to give 3×10
9
different molecules, well beyond the size that currently can be screened on available computers, in a reasonable amount of time. Furthermore, most pharmaceutically interesting molecules are flexible, adding an additional level of complexity to the problem. There exist methods that attempt to deal with flexible molecules by constrained optimization, yet these are computationally expensive—the optimization is a computationally demanding overhead on the database search itself. For example using the method of “template-forcing”, in which an attempt is made to force each analog to fit the desired conformation, databases that can be virtually screened within a reasonable amount of time are on the orders of magnitude of 10
5
different compounds. The optional approach is to represent each flexible molecule as a set of discrete conformations. Thus in the above example if the 18 sidechains are represented by a rotamer library of 10 conformations for each, the result will be a database of 3×10
15
entities, representing all possible discrete conformations of the 3×10
9
different molecules. Since with currently available tools it is not feasible to virtually scan even the smaller library of 3×10
9
molecules, a tool that enables the construction and screening of libraries of this size range within reasonable time is of high practical value.
The necessity to scan extraordinarily large number of entities in a search space also arises in the field of protein sequence design. In protein sequence design a large number of sequence combinations needs to be evaluated in searching for the one that optimally lends itself to a particular structure. One method that has been applied to this problem, the Dead-End Elimination algorithm, is related to the art of the present invention in that it utilizes a library of discrete conformations for each of the amino-acid side chains, and defines mathematical criteria for eliminating the vast majority of combinatorial possibilities without actually considering them formally. This algorithm has been successfully applied to the problem of protein design [B. I. Dahiyat and S. L. Mayo, De Novo Protein Design: Fully Automated Sequence Selection.
Science
278,82(1997); PCT application No. WO 98/47089].
Thus, there is a widely recognized need for, and it would be highly advantageous to have, a method for constructing very large virtual databases of molecules which are potentially pharmaceutically useful, and for screening these molecules for the existence of a pharmacophore, representing the desired interactions of the useful molecule with one or more structures in the body of the subject.
SUMMARY OF THE INVENTION
The present invention features a method for constructing a potentially pharmaceutically useful molecule that contains a desired pharmacophore, associated with a specific biological activity.
One aspect of the present invention is a method for constructing a virtual combinatorial library (VCL), which is a set of abstract super-structures, none of which is a physically realizable entity. Each super-structure features a single chemical scaffold holding all possible substituents at all possible substituent attachment points, concurrently. This VCL represents a set of physically realizable discrete conformations of a defined set of molecular entities. This set may be very large, representing more than 10
20
different 3-dimensional structures by a small number of such super-structures.
Another aspect of the present invention is a method for virtually screening this library for the existence of molecules that display a desired, predefined molecular structure, and in particular a pharmacophore.
The VCL is constructed from a virtual library of scaffolds, for example constrained peptidomimetic backbones, and a virtual library of substituents that can be placed at each of a set of predefined attachment positions on each scaffold. The VCL is constructed by placing all rotamers from the virtual library of substituents onto each of the attachment po
Olender Roberto
Rosenfeld Rakefet
Graeser D'vorah
Horlick Kenneth R.
Peptor Ltd.
Strzelecka Teresa
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