Inhibitor scaffold for the inhibition of the enzyme phosphoenolpyruvate carboxykinase

Abstract

A PEPCK inhibitor can include identifying a molecule that has a size capable of fitting into and interacting with the PEPCK binding site and at least one of the following: (a) a first terminal substituent having co-planar atoms acting as metal ligands to the active site metal ion PEPCK; (b) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent includes a neutral carbon center or include an oxygen, sulfur, selenium, or other atom with similar physiochemical properties; (c) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent is devoid of an electropositive atom or substituents; or (d) a second terminal substituent opposite of the first terminal substituent, said second terminal substituent having an atom that is a hydrogen boding acceptor and/or is negatively charged.

1 . A compound for inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in a subject, the compound comprising:
 a molecule configured for interacting with a biding site of PEPCK so as to inhibit PEPCK, said molecule being characterized by having a size capable of fitting into and interacting with the PEPCK binding site and at least one of the following:
 (a) a first terminal substituent having co-planar atoms acting as metal ligands to the active site metal ion of PEPCK; 
 (b) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent includes a neutral carbon center or include an oxygen, sulfur, selenium, or other atom with similar physiochemical properties, 
 (c) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent is devoid of an electropositive atom or substituents; or 
 (d) a second terminal substituent opposite of the first terminal substituent, said second terminal substituent having an atom that is a hydrogen boding acceptor and/or is negatively charged. 
   
     
     
         2 . A compound as in  claim 1 , wherein the PEPCK inhibitor includes at least two of (a), (b), (c), or (d). 
     
     
         3 . A compound as in  claim 2 , wherein the PEPCK inhibitor includes at least three of (a), (b), (c), or (d). 
     
     
         4 . A compound as in  claim 3 , wherein the PEPCK inhibitor includes (a), (b), (c), and (d). 
     
     
         5 . A compound as in  claim 1 , wherein at least one of the co-planar atoms of the first terminal substituent interacts with S286. 
     
     
         6 . A compound as in  claim 1 , wherein the compound interacts with at least one of R87 or R405. 
     
     
         7 . A compound as in  claim 1 , wherein the PEPCK inhibitor includes features one of Formula A, B, C, or D, or salt thereof, acid thereof, derivative thereof or combinations thereof so as to interact with M2+ active metal site of PEPCK through interactions (a) and (b): 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound as in  claim 7 , wherein the PEPCK inhibitor has a structure of Formula C or derivative or salt thereof. 
     
     
         9 . A compound as in  claim 1 , wherein the PEPCK inhibitor has a structure of Formula E or derivative or salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R1 is a hydrogen, halogen, Cl, F, CH 3 , CH 3 CH 2 , or higher or lower substituted or unsubstituted straight chain or branched aliphatic (e.g., C1-C10); 
       R2 is hydrogen, CH 3 CH 2 , or C1-C10 substituted or unsubstituted straight chain or branched aliphatic; 
       R3 is a carboxylic acid, amide, Formula F, sulphate, phosphate, or other hydrogen bond donor or has a positive charge; 
       X can be C, O, or N, such that X is a hydrogen bond donor; 
       and n can be 0, 1, 2, or 3. 
     
     
         10 . A compound as in  claim 9 , wherein at least one of R1 or R2 is electronegative and not electropositive. 
     
     
         11 . A compound as in  claim 9 , wherein the PEPCK inhibitor has a structure of Formula G or derivative or salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound as in  claim 1 , wherein the PEPCK inhibitor is devoid of being characterized by at least one of the following:
 a methyl or methylene center which is incapable of interacting with R405;   a size incapable of fitting within the binding pocket framed by R87, K244, G237, F333, R405, N403 and/or Y235;   a steric conflict with F333; or   a positively charged functional group incompatible with a positively charged active site of PEPCK.   
     
     
         13 . A composition for inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in a subject, the composition comprising:
 a pharmaceutically acceptable carrier; and   a therapeutically effective amount of the PEPCK inhibitor of  claim 1 .   
     
     
         14 . A composition for inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in a subject, the composition comprising:
 a pharmaceutically acceptable carrier; and   a therapeutically effective amount of the PEPCK inhibitor of  claim 8 .   
     
     
         15 . A composition for inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in a subject, the composition comprising:
 a pharmaceutically acceptable carrier; and   a therapeutically effective amount of the PEPCK inhibitor of  claim 9 .   
     
     
         16 . A method for inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in a subject, the method comprising:
 administering to the subject a composition having a PEPCK inhibitor characterized by having a size capable of fitting into and interacting with the PEPCK binding site and at least one of the following:
 (a) a first terminal substituent having co-planar atoms acting as metal ligands to the active site metal ion PEPCK; 
 (b) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent includes a neutral carbon center or include an oxygen, sulfur, selenium, or other atom with similar physiochemical properties, 
 (c) at least one of an atom or substituent at positions 2 or 3 from the first terminal substituent is devoid of an electropositive atom or substituents; or 
 (d) a second terminal substituent opposite of the first terminal substituent, said second terminal substituent having an atom that is a hydrogen boding acceptor and/or is negatively charged. 
   
     
     
         17 . A method as in  claim 16 , where the PEPCK inhibitor is administered in a therapeutically effective amount for treating, inhibiting, and/or hyperglycemia in the subject. 
     
     
         18 . A method as in  claim 17 , wherein the subject is a diabetic patient. 
     
     
         19 . A method as in  claim 16 , wherein the PEPCK inhibitor has a structure of Formula E or derivative or salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R1 is a hydrogen, halogen, Cl, F, CH 3 , CH 3 CH 2 , or higher or lower substituted or unsubstituted straight chain or branched aliphatic (e.g., C1-C10); 
       R2 is hydrogen, CH 3 CH 2 , or C1-C10 substituted or unsubstituted straight chain or branched aliphatic; 
       R3 is a carboxylic acid, amide, Formula F, sulphate, phosphate, or other hydrogen bond donor or has a positive charge; 
       X can be C, O, or N, such that X is a hydrogen bond donor; 
       and n can be 0, 1, 2, or 3. 
     
     
         20 . A method as in  claim 19 , wherein the PEPCK inhibitor has a structure of Formula G or derivative or salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A method as in  claim 19 , wherein the PEPCK inhibitor has a structure of Formula C: