Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Chemical analysis
Reexamination Certificate
1997-08-22
2001-01-30
Shah, Kamini (Department: 2857)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Chemical analysis
C702S021000, C702S027000, C702S030000
Reexamination Certificate
active
06182016
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to molecular classification approaches useful to generate comparisons that can be applied to combinatorial chemistry applications or other applications where the determination of similarities and differences of molecules is desirable.
BACKGROUND OF THE INVENTION
The selection of useful chemical compounds for any application can be a time consuming and expensive task. Typically, the first step is to look for signs of the desired activity in any compound available. The compounds can be natural or synthetic. Starting from a promising compound, the compound can then be modified, traditionally through one-at-a-time modifications to the structure. In the drug industry, for example, many years and hundreds of millions of dollars may be required to bring a drug to market. Therefore, attempts have been made to make the process more efficient.
More systematic approaches, generally termed combinatorial chemistry, are based on having combinatorial collections or libraries of compounds that can be screened for activity. A library can be constructed based on general chemical principles. The library is then input into a systematic development process. Examples of systematic development processes include a parallel synthesis approach and a split-and-mix synthesis approach.
In the parallel synthesis approach, the building blocks for a study are placed in separate reaction vessels, generally wells of a microtitre plate. The appropriate syntheses can be carried out in each well to produce a set of products. These can then be used in efficacy screening, toxicity studies, and the like. Efficacy screening can involve tests for biological activity or any other chemical property.
In a split-and-mix synthesis, a series of first reactants are attached to polystyrene beads. These attached reactants are mixed together and split into a series of vessels, tubes or wells. A different second reactant is added to each vessel. If a third reactant is involved, the second group is again mixed together and split. A different third reactant is added to the tubes containing the second mixtures. The most potent of the final mixtures are determined. A variety of techniques can be used to ascertain the most potent combination.
While drug design is a significant application of these techniques, these combinatorial chemistry approaches can be used for the production of chemicals for any application. For example, they have also been used to identify high temperature superconductors, liquid crystals for flat panel displays, and materials for constructing batteries. The assays incorporated into the techniques are appropriate for the type of compound desired. Basic to the application of these development programs is the construction of a suitable library of chemicals.
SUMMARY OF THE INVENTION
The present methods provide an accurate and efficient approach for computing three-dimensional descriptors for three-dimensional substructure searching, similarity searching, combinatorial chemistry library design and for diversity management. Molecular descriptors are of central importance for developing high throughput screening, especially for drug lead searching and drug lead optimization. The present approach is based on geometrical constructs that provide detailed local structural information along with relationships between the neighboring local structures. An efficient and systematic characterization can be performed based on the geometrical construction. Considerable versatility is provided to adjust the desired features of the characterization and the important features for comparison between molecules.
In a first aspect, the invention features a method of classifying molecules for assisting with the selection of compounds for further study, the method including the steps of:
(a) forming a 3-dimensional body by placing a potentially overlapping ball around each atom or group of atoms of the molecule, the ball having a a radius selected for the particular type of atom or group of atoms;
(b) generating structural descriptors reflecting information about neighboring atoms or groups of atoms, the structural descriptors relating to the Voronoi diagram corresponding to the 3-dimensional body; and
(c) classifying the molecule using the descriptors.
The descriptors can be obtained by performing a weighted Delaunay triangulation to obtain topological elements associated with the molecular structure. The topological elements can be selected from the group consisting of a vertices, edges, triangles, tetrahedrons and combinations thereof.
Furthermore, an additional descriptor can be associated with each atom or group of atoms. The additional descriptor can relate to a property selected from the group consisting of polarity, hydrophobicity, hydrophilicity, chemical reactivity, location relative to the surface of the molecule, location relative to the convex hull of the three-dimensional body, local concavity of the surface of the molecule and relationship to cavities. Alternatively, the additional descriptor can be selected from the group consisting of the characteristic alpha value of the structural descriptors, the star relation or the link relation.
In another aspect, the invention features a method of classifying molecules for assisting with the selection of compounds for further study, the method including the steps of:
(a) performing a Delaunay triangulation based on a 3-dimensional body associated with the structure of the molecule based on the atomic centers to obtain a set of topological elements including, at least, triangles and tetrahedra;
(b) classifying the molecule based on these topological elements.
In another aspect, the invention features a method of identifying molecules that are similar to a known compound comprising the steps of:
(a) classifying the known compound based on a classification system of the invention;
(b) identifying significant elements within the classification scheme in terms of classification parameters;
(c) determining classifications of relevant molecules having the identified classification parameters similar or identical with the known compound; and
(d) establishing the structure of a molecule corresponding to the determined classifications of relevant molecules.
The method of identifying molecules that are similar to a known compound can further include the step of evaluating the chemical properties of a chemical compound corresponding to the established structure.
In another aspect, the invention features a method of evaluating the degree of similarity between two molecules comprising the steps of:
(a) classifying the two molecules based on a classification method of the invention; and
(b) determining the degree of similarity between the two molecules based on a comparison of the descriptors determined for each of the two molecules.
In another aspect, the invention features a method of selecting a diverse group of compounds for evaluation of efficacy from a collection of relevant molecules, the method including the steps of:
(a) determining a range of classifications for an evaluated set of compounds, using a classification method of the invention;
(b) identifying significant elements within the classification scheme in terms of classification parameters; and
(c) selecting based on the classification parameters a diverse set of compounds within the evaluated set of compounds.
In another aspect, the invention features a method of selecting and evaluating the efficacy of a chemical compound, the method including the steps of:
(a) classifying a known compound based on a classification method of the invention;
(b) identifying a compound from a group of compounds having a similar classification, with respect to significant features, to the known compound based on the same classification method used in step (a); and
(c) evaluating efficacy of the identified molecule using a chemical or pharmacological test.
The invention further features an electronic storage device including a storage medium, where the storage medium stores a computer program for impleme
Edelsbrunner Herbert
Liang Jie
Bui Bryan
Dardi Peter S.
Shah Kamini
Westerman, Champlin & Kelly, P.A.
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