Claims
- 1. A system for predicting pharmacokinetic properties of a proposed biologically active substance of known chemical structure based on correlation of the chemical structures of known biologically active substances, their known respective pharmacokinetic properties and their empirically defined chemical structure/membrane affinity relationships, said system comprising
a data storage device having in computer readable format a data set comprising chemical structures of a multiplicity of control compounds comprising biologically active substances, and for each compound, numeric values relating to the affinity of said compound to at least a negatively charged membrane mimetic surfaces and to a neutral membrane mimetic surface, and a numeric value relating to a known pharmacokinetic property, if any, of said compound; a data entry device for entering the chemical structure of the proposed substance or other search parameters in computer readable format; a programmable microprocessor in communication with said data entry device and said data storage device, said microprocessor programmed to compare the chemical structure of the proposed substance entered into the data entry device with chemical structures in the data set to identify the chemical structures in the data set having a predetermined degree of similarity with the structure of the proposed substance; and an output device in communication with the microprocessor and capable of reporting, upon user request, the chemical structures or other identification of control compounds, if any, having the predetermined degree of similarity with the chemical structure of the proposed substance and other data stored for said identified control compound(s).
- 2. The system of claim 1 wherein the microprocessor is programmed to report the numeric values for the pharmacokinetic properties of the control compound(s) identified to have the predetermined degree of structural similarity.
- 3. The system of claim 1 wherein the microprocessor is programmed to identify control compounds having membrane binding characteristics similar to the membrane binding characteristic of the control compound(s) identified to have the predetermined degree of structure similarity to that of the proposed substance.
- 4. The system of claim 1 wherein the identification of control compounds having similar membrane binding characteristics is accomplished by calculating nearest neighbors to the point (XS, YS) in an array of points (XC, YC) wherein XS, YS are the numeric values relating to the affinity of a control compound having the predetermined degree of structural similarity for a neutral membrane mimetic surface and a negatively charged membrane mimetic surface, respectively, and XC, YC are the numeric values relating to the affinity of the respective control compounds for a neutral membrane mimetic surface and a negatively charged membrane mimetic surface, respectively.
- 5. The system of claim 2 wherein the identification of control compounds having similar membrane binding characteristics is accomplished by calculating nearest neighbors to the point (XS, YS) in an array of points (XC, YC) wherein XS, YS are the numeric values relating to the affinity of a control compound having the predetermined degree of structural similarity for a neutral membrane mimetic surface and a negatively charged membrane mimetic surface, respectively, and XC, YC are the numeric values relating to the affinity of the respective control compounds for a neutral membrane mimetic surface and a negatively charged membrane mimetic surface, respectively.
- 6. The system of claim 1 wherein the microprocessor is programmed to report the numeric values for the pharmacokinetic properties of the control compounds having membrane binding characteristics similar to the membrane binding characteristics of the control compound(s) having the predetermined degree of chemical structure similarity.
- 7. The system of claim 1 wherein the microprocessor is programmed to compare the membrane binding characteristics of the control compound(s) identified to have the predetermined degree of chemical structural similarity with an empirically defined correlation between membrane binding characteristics and numeric values for each of several pharmacokinetic properties and to report the correlation predicted numeric values for each of the pharmacokinetic properties.
- 8. A method for estimating the affinity of a test compound to membrane mimetic surface or a pharmacokinetic property of the test compound related to a membrane affinity, said method comprising the steps of
empirically defining a correlation between the structure of control compounds comprising drug substances and their respective affinities for membrane mimetic surfaces and preparing a data set comprising an array of control compound structures, values for their respective affinities for membrane mimetic surfaces, and values for their pharmacokinetic properties, if known; conducting a search of the compound structures in the data set to identify control compounds having a structure with a predetermined degree of similarity with that of the test compound, and assigning the values for the membrane affinities and/or the pharmacokinetic properties of the identified control compound(s) as an estimate of the corresponding values and properties for the test compound.
- 9. A method for predicting pharmacokinetic properties for a proposed biologically active substance of known chemical structure, said method comprising the steps of
selecting a database including, in computer readable format, chemical structures for a multiplicity of control compounds, said control compounds comprising known biologically effective compounds and for those known effective compounds having known pharmacokinetic properties numeric values relating to at least a portion of said pharmacokinetic properties; searching the database for compounds having a chemical structure similar to that of the proposed substance and identifying those control compounds that have a predetermined degree of similarity to the proposed substance; identifying the pharmacokinetic properties of the control compounds having the predetermined degree of structural similarity, if any, to the proposed substance, and if no compounds are identified as having the predetermined degree of structural similarity, repeating the searching step using a lower predetermined degree of similarity until at least one control compound in the database is identified; and reporting the pharmacokinetic properties of the identified control compound(s) to predict the pharmacokinetic properties of the proposed substance.
- 10. A method for designing chemical structure modifications of a hit compound found to have target receptor binding activity in vitro to produce proposed chemical structures for test substances having improved pharmacokinetic properties relative to those of said hit compound, method comprising the step of
selecting a database, including in computer readable format, structures for a multiplicity of control compounds, said compounds comprising known biologically effective substances having predetermined pharmacokinetic properties, and for each compound numeric values relating to the predetermined pharmacokinetic properties, if known, and numeric values relating to the affinity of said compound to at least a neutral membrane mimetic surface and a negatively charged membrane mimetic surface; obtaining numeric values relating to the affinity of the hit compound to each of said membrane mimetic surfaces; correlating the respective known pharmacokinetic properties of the control compounds with their respective positions on a plot of an array of the points (XA, YB) for at least a subset of the control compounds in the database wherein XA is the numeric value relating to the affinity of the compound to one membrane mimetic surface and YB is the numeric value relating to the affinity of the compound to the other membrane mimetic surface; correlating the respective positions of the points (XA, YB) in the array with chemical structural features of the respective control compounds represented by the respective points; identifying the position of the point (HA, HB) in the array of points (XA, YB) wherein HA is the numeric value relating to the relative affinity of the hit compound to one membrane mimetic surface and HB is the numeric value relating to the relative affinity of the hit compound to the other membrane mimetic surface; identifying potential modifications of the chemical structure of the hit compound, with view of the respective correlations of chemical structure and array position and pharmacokinetic properties and array position to produce a predictable change in relative membrane binding affinities and pharmacokinetic values correlated therewith; and preparing the compound represented by the modified chemical structure and assaying same for target macromolecule binding activity, and, optionally, membrane binding affinities.
- 11. A method for estimating pharmacokinetic properties of a test drug substance, said method comprising the steps of
identifying two or more membrane mimetic surfaces including a first membrane mimetic surface having a negatively charged surface and a second substantially neutral membrane mimetic surface; identifying a set of control compounds comprising drug substances having known pharmacokinetic properties and each pharmacokinetic property being quantified for each control compound by a numeric value within a range of numeric values relating to the pharmacokinetic property; defining for each control compound a numeric value related to its affinity for each membrane mimetic surface; defining for the test drug substance a numeric value related to its affinity for each membrane mimetic surface for each pharmacokinetic property, identifying a subset of control compounds having similar pharmacokinetic property related numeric values and similar membrane affinity related values to establish a correlation between a subrange of pharmacokinetic property related values and a subrange of membrane affinity related values; comparing the membrane affinity related numeric values of the test drug substance with the correlated subranges of membrane affinity related values and pharmacokinetic property related values, and with respect to each pharmacokinetic property, identifying the subrange of numeric values related to that pharmacokinetic property correlated with the subrange of membrane affinity related numeric values for each membrane mimetic surface bracketing the respective membrane affinity related numeric values for the test drug substance; and selecting the subrange of pharmacokinetic property related numeric values for each pharmacokinetic property best matching the membrane affinity related numeric value for the test drug substance.
- 12. A method for estimating pharmacokinetic properties of a test drug substance, said method comprising the steps of
identifying two or more membrane mimetic surfaces including a first membrane mimetic surface having a negatively charged surface and a second substantially neutral membrane mimetic surface; identifying a set of control compounds comprising drug substances having known pharmacokinetic properties and each pharmacokinetic property being quantified for each control compound by a numeric value within a range of numeric values relating to the pharmacokinetic property; defining for each control compound a numeric value related to its affinity for each membrane mimetic surface; defining for the test drug substance a numeric value related to its affinity for each membrane mimetic surface; for each membrane mimetic surface or for a subset of the membrane mimetic surface, establishing, if possible, a mathematical correlation of membrane affinity related numeric values for the control compounds or a subset thereof with the numeric values relating to the respective pharmacokinetic properties using said correlation to calculate estimated numerical values for the respective pharmacokinetic properties for the test drug substance.
- 13. A method for discovery of biologically effective compounds candidates having both potential for binding to a macromolecule recognized to be the endogenous target of a set of known effective substances and favorable pharmacokinetic properties, said method comprising the step of
identifying chemical structural or substructural characteristics of said known biologically effective substances, conducting a structure similarity search of a database comprising chemical structures of commercially available compounds to identify structures in the database of compounds having a threshold predetermined degree of structural similarity to at least one of the known effective substances; comparing the identified structures with those in a data set comprising the chemical structures of known effective substances and values corresponding to the relative affinity of said substances for at least two membrane mimetic surfaces and values corresponding to their pharmacokinetic properties, to eliminate, based on their probable lack of pharmacokinetic properties required for biological efficacy, at least a portion of those compounds identified to have the predetermined degree of structural similarity; and testing at least a subset of the compounds not eliminated by the correlated comparison for binding affinity to the macromolecular target.
- 14. The method of claim 1 wherein the proposed biologically active substance is selected from the group consisting of a drug, a herbicide and a pesticide.
- 15. The method of claim 14 wherein the proposed biologically active substance is a drug.
- 16. The method of claim 9 wherein the proposed biologically active substance is selected from the group consisting of a drug, a herbicide and a pesticide.
- 17. The method of claim 16 wherein the proposed biologically active substance is a drug.
- 18. The method of claim 10 wherein the proposed biologically active substance is selected from the group consisting of a drug, a herbicide and a pesticide.
- 19. The method of claim 18 wherein the proposed biologically active substance is a drug.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/281,749, filed Apr. 5, 2001 expressly incorporated by reference herein.
Provisional Applications (1)
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Number |
Date |
Country |
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60281749 |
Apr 2001 |
US |