Design of drugs involving receptor-ligand-DNA interactions

Abstract

It has been discovered that the degree of hormonal activity of candidate ligands correlates better with degree of fit into DNA than with the strength of receptor binding, and that the receptors in the steroid/thyroid hormone/vitamin A and D family alter the physiochemical properties of DNA and in concert with other transcription factors facilitate insertion of the ligand into DNA. As a result, the magnitude of the response is a function of the structure of the ligand as it related to insertion and fit into the DNA and the specificity of the response is a function of the stereochemistry of the receptor through binding to both the ligand and to the DNA. Based on these discoveries, a method is described herein for identifying drugs having increased activity as compared with the natural ligand for receptors such as the estrogenic receptors.

I claim:  
     
         1 . A method for designing molecules having biological activity comprising 
 designing compounds which are complementary to a double stranded DNA helical structure;    determining the energy of interaction between the compound and the DNA in the presence of specific biological receptors; and    selecting compounds having an equal or lower energy of interaction than the natural ligands for the specific biological receptors.    
     
     
         2 . The method of  claim 1  wherein the receptor binds to a compound selected from the group consisting of steroids, thyroid hormones, vitamins, phytohormones, peptide hormones, neurotransmitters, prostaglandins, and sugars.  
     
     
         3 . The method of  claim 1  wherein the compound has a cyclopentanophenanthrene motif.  
     
     
         4 . The method of  claim 1  wherein the compound is complementary to an unwound cavity within a DNA helix.  
     
     
         5 . The method of  claim 1  wherein the compound is complementary to a cavity in DNA formed by shifting a base in an unwound site.  
     
     
         6 . The method of  claim 1  wherein the compound is complementary to a cavity formed in DNA by removing a nucleotide base.  
     
     
         7 . The method of  claim 1  wherein the compound is a receptor antagonist.  
     
     
         8 . The method of  claim 7  wherein the compound is reproductive hormone antagonist.  
     
     
         9 . A compound having biological activity isolated by the process comprising, 
 designing compounds which are complementary to a double stranded DNA helical structure;    determining the energy of interaction between the compound and the DNA in the presence of specific biological receptors; and    selecting those compounds having an equal or lower energy of interaction than the natural ligands for the specific biological receptors.    
     
     
         10 . The compound of  claim 9  wherein the receptor binds to a compound selected from the group consisting of steroids, thyroid hormones, vitamins, phytohormones, peptide hormones, neurotransmitters, prostaglandins, and sugars.  
     
     
         11 . The compound of  claim 9  wherein the compound has a cyclopentanophenanthrene motif.  
     
     
         12 . The compound of  claim 9  wherein the compound is complementary to an unwound cavity within a DNA helix.  
     
     
         13 . The compound of  claim 9  wherein the compound is complementary to a cavity in DNA formed by shifting a base in an unwound site.  
     
     
         14 . The compound of  claim 9  wherein the compound is complementary to a cavity formed in DNA by removing a base.  
     
     
         15 . The compound of  claim 9  having estrogenic activity.  
     
     
         16 . The compound of  claim 9  wherein the compound is a receptor antagonist.  
     
     
         17 . The compound of  claim 16  wherein the compound is a reproductive hormone antagonist.  
     
     
         18 . A pharmacophore comprising, 
 a three-dimensional array of points defining a specific shape and volume, wherein said three-dimensional array of points is the aggregate average shape of a plurality of molecules when optimally fit into an unwound DNA site, said molecules possessing the same or similar biological activity.    
     
     
         19 . A biologically active compound designed using a pharmacophore of  claim 18 , wherein the template identifies areas of structure and charge responsible for fit into DNA.  
     
     
         20 . A method for creating a pharmacophore comprising the steps of: 
 determining the optimal fit of a plurality of compounds having the same or similar biological activity into nucleic acid sequences such that the lowest energy of interaction and best steric fit are obtained;    aligning the compounds relative to the heteroatoms on the nucleic acids; and    defining a three dimensional shape representing the aggregate average shape resulting from said alignment of the compounds.    
     
     
         21 . The method of  claim 20 , wherein the nucleic acid sequence is selected from the group consisting of deoxyribonucleic acid, double stranded deoxyribonucleic acid, ribonucleic acid, complexes of deoxyribonucleic acid and ribonucleic acid, and apurinic and apyrimidinic sites.  
     
     
         22 . The method of  claim 20 , wherein the nucleic acid is deoxyribonucleic acid.  
     
     
         23 . A method of screening a molecule for bioactivity or toxicity wherein the molecule is examined for the ability to fit into a pharmacophore comprising the steps of: 
 measuring the energy of interaction when the molecule is fitted into the pharmacophore; and    comparing the energy of interaction of the molecule to a predetermined energy of activation that correlates to a biological activity.    
     
     
         24 . The method of  claim 23  wherein the pharmacophore is selected from the group consisting of an estrogen pharmacophore, an antiestrogen pharmacophore, an androgen pharmacophore, a thyroid hormone pharmacophore, and toxicophore.  
     
     
         25 . A method for screening a molecule for toxicity wherein the molecule is examined for the ability to fit into a toxicity pharmacophore comprising the steps of 
 measuring the energy of interation when the molecule is fitted into the pharmacophore; and    comparing the energy of interaction of the molecule to a predetermined energy of activation that correlates to a toxic activity.    
     
     
         26 . A method of designing a molecule with a desired biological activity comprising the step of determining the structure of a molecule which will have a minimal predetermined energy of activation when fitted into a pharmacophore with a desired activity.