Abstract: A computerized procedure for aligning molecules for use in CoMFA or other 3D QSAR methodologies does not rely on fragmentation of the molecules instead, aligning molecules based upon comparison to identified template molecules. Initially an anchor bond is identified in the candidate and template molecule that have similar atoms at each end of the bonds. The anchor bond need not be an acyclic bond. The candidate molecule is overlaid onto the template molecule by aligning the anchor bonds. Starting and working away from the anchor bond, matching atoms or atom types between the candidate and template molecule are identified. Once all matching atoms have been identified, the 3D coordinates of the template atoms are assigned to the corresponding atoms in the candidate molecule to place the candidate molecule into alignment.

Abstract: A computerized procedure for aligning molecules for use in CoMFA or other 3D QSAR methodologies does not rely on fragmentation of the molecules instead, aligning molecules based upon comparison to identified template molecules. Initially an anchor bond is identified in the candidate and template molecule that have similar atoms at each end of the bonds. Unlike prior art methods, the anchor bond need not be an acyclic bond. The candidate molecule is overlaid onto the template molecule by aligning the anchor bonds. Starting and working away from the anchor bond, matching atoms or atom types between the candidate and template molecule are identified. Multiple layers of atomic connections are evaluated for matches. The atoms may or may not be contained within ring structures. Once all matching atoms have been identified, the 3D coordinates of the template atoms are assigned to the corresponding atoms in the candidate molecule to place the candidate molecule into alignment.

Abstract: The computational drug discovery method disclosed herein permits a user to specify a three dimensional representation of a molecular fragment derived from a query molecule involved in a drug interaction that then serves as a template to which fragments derived from molecules in database libraries may be aligned. The likely activity of the substitution of the fragment from the database library for the fragment from the query molecule may then be predicted by appropriate shape characterization and CoMFA analysis. The spatial three dimensional representation of the query fragment may be developed from binding data, crystallographic data, modeling data, or any other biophysical or biochemical technique.

Abstract: The computational drug discovery method disclosed herein permits a user to specify a three dimensional representation of a molecular fragment derived from a query molecule involved in a drug interaction that then serves as a template to which fragments derived from molecules in database libraries may be aligned. The likely activity of the substitution of the fragment from the database library for the fragment from the query molecule may then be predicted by appropriate shape characterization and CoMFA analysis. The spatial three dimensional representation of the query fragment may be developed from binding data, crystallographic data, modeling data, or any other biophysical or biochemical technique. The alignment method of the present invention supplants the topomeric alignment taught in U.S. Pat. No. 7,329,222 and U.S. application Ser. No. 12/045,511 for use in computing a CoMFA 3D QSAR.

Abstract: A forward synthetic method is described that utilizes recursive application of established organic chemical reactions to derive more complex synthons from available reagents than are available from the reagent synthons themselves. The product of each reaction serves as the starting point for further reactions thereby permitting the generation of multiple complex molecular structures. This synthon generation procedure typically yields 20 ? 30 new structures within the limits of easily accessible syntheses based upon each starting reagent. More complex syntheses yield even more structures. The generated synthons are characterized with a molecular structural descriptor possessing a neighborhood property and can be further characterized with features. The synthons are searched for three dimensional shape and feature similarity to molecular fragments derived from query molecules, typically pharmacological molecules of interest.

Abstract: A CoMFA 3D QSAR shape analysis may be performed on molecules arising from the same activity series that may be decomposed/viewed as assemblies of discrete identifiable subunits. The disclosed method provides for identifying in databases of whole molecules those molecular subunits that possess the same shape or shape and feature characteristics as the subunits of molecules used to perform the CoMFA analysis. Additionally, the method provides for estimation of the likely biological activity of molecules assembled from the subunits identified in the molecular database.

Abstract: A forward synthetic method is described that utilizes recursive application of established organic chemical reactions to derive more complex synthons from available reagents than are available from the reagent synthons themselves. The product of each reaction serves as the starting point for further reactions thereby permitting the generation of multiple complex molecular structures. This synthon generation procedure typically yields 20 ? 30 new structures within the limits of easily accessible syntheses based upon each starting reagent. More complex syntheses yield even more structures. The generated synthons are characterized with a molecular structural descriptor possessing a neighborhood property and can be further characterized with features. The synthons are searched for three dimensional shape and feature similarity to molecular fragments derived from query molecules, typically pharmacological molecules of interest.

Abstract: The static and electrostatic interaction energy fields between probe atoms and the atoms of a topomerically aligned fragment placed in a three-dimensional grid may be used to derive a CoMFA model. The topomeric CoMFA model coefficients may be used to predict partial activity values for fragments not derived from molecules of the activity series. The partial activities can be summed to provide a predicted activity for all fragment positions of the activity series molecules. A Virtual Library in which topomerically aligned fragments are associated with their respective steric and electrostatic interaction energies can be searched for fragments similar in shape to the fragments derived from the molecules of the activity series. The identified fragments can be used with the topomeric CoMFA coefficients to predict their activity if used in the molecular activity series.

Abstract: Heterogeneous compound databases can be searched for compounds which are likely to have the same biological activity as a known (query) molecule. Query molecules and the molecules in the database are split into fragments according to common fragmentation rules. Fragments are aligned in a uniform conformation according to a topomeric alignment process and interaction energy fields, typically steric fields, between a probe and the fragment atoms are generated to capture the fragment shapes. Comparison of the fields for the query fragments with the fields for the database compound fragments yields a measure of shape similarity. Searches for similarly shaped substructures and cores can also be readily accomplished. Pharmacophoric style features can be defined for the topomerically aligned fragments but with user specified weighting of the importance of each. Differences in features are defined with the same dimensionality as shape so that both shape and features can be used to search.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: The problem of how to select out of a large chemically accessible universe molecules representative of the diversity of that universe is resolved by the discovery of a method to validate molecular structural descriptors. Using the validated descriptors, optimally diverse subsets can be selected. In addition, from the universe, molecules with characteristics similar to a selected molecule can be identified. The validated descriptors also enable the generation of a huge virtual library of potential product molecules which could be formed by combinatorial arrangement of structural variations and cores. In this virtual library it is possible to search billions of possible product compounds in relatively short time frames.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: The static and electrostatic interaction energy fields between probe atoms and the atoms of a topomerically aligned fragment placed in a three-dimensional grid may be used to derive a CoMFA model. The topomeric CoMFA model coefficients may be used to predict partial activity values for fragments not derived from molecules of the activity series. The partial activities can be summed to provide a predicted activity for all fragment positions of the activity series molecules. A Virtual Library in which topomerically aligned fragments are associated with their respective steric and electrostatic interaction energies can be searched for fragments similar in shape to the fragments derived from the molecules of the activity series. The identified fragments can be used with the topomeric CoMFA coefficients to predict their activity if used in the molecular activity series.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: Heterogeneous compound databases can be searched for compounds which are likely to have the same biological activity as a known (query) molecule. Query molecules and the molecules in the database are split into fragments according to common fragmentation rules. Fragments are aligned in a uniform conformation according to a topomeric alignment process and interaction energy fields, typically steric fields, between a probe and the fragment atoms are generated to capture the fragment shapes. Comparison of the fields for the query fragments with the fields for the database compound fragments yields a measure of shape similarity. Searches for similarly shaped substructures and cores can also be readily accomplished. Pharmacophoric 10i;.: style features can be defined for the topomerically aligned fragments but with user specified weighting of the importance of each. Differences in features are defined with the same dimensionality as shape so that both shape and features can be used to search.

Abstract: The problem of how to select out of a large chemically accessible universe molecules representative of the diversity of that universe is resolved by the discovery of a method to validate molecular structural descriptors. Using the validated descriptors, optimally diverse subsets can be selected. In addition, from the universe, molecules with characteristics similar to a selected molecule can be identified. The validated descriptors also enable the generation of a huge virtual library of potential product molecules which could be formed by combinatorial arrangement of structural variations and cores. In this virtual library it is possible to search billions of possible product compounds in relatively short time frames.

Abstract: The problem of how to select out of a large chemically accessible universe molecules representative of the diversity of that universe is resolved by the discovery of a method to validate molecular structural descriptors. Using the validated descriptors, optimally diverse subsets can be selected. In addition, from the universe, molecules with characteristics similar to a selected molecule can be identified. The validated descriptors also enable the generation of a huge virtual library of potential product molecules which could be formed by combinatorial arrangement of structural variations and cores. In this virtual library it is possible to search billions of possible product compounds in relatively short time frames.