Dna methyltransferase 1 transition state structure and uses thereof

Abstract

Methods and systems for obtaining inhibitors of human DNA methyltransferase 1 (DNMT1) are disclosed where the methods involve designing compounds that resemble the DNMT1 transition state.

What is claimed is: 
     
         1 . A computer-implemented, experimentally-guided kinetic isotope effect method for detecting or screening for a compound that is an inhibitor of human DNA methyltransferase 1 (DNMT1), the method comprising the steps of:
 (i) inputting into the computer values for the molecular electrostatic potential at a van der Waals surface computed from a wave function of a DNMT1 transition state and values for a geometric atomic volume of the DNMT1 transition state, wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
         (ii) using chemical logic aided by computer design to obtain a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state; 
         (iii) optionally synthesizing the compound; and 
         (iv) optionally testing the compound for inhibitory activity to DNMT1; 
         to thereby detect or screen for a compound that is an inhibitor of DNMT1. 
       
     
     
         2 . A method of detecting, screening for or designing an inhibitor of human DNA methyltransferase 1 (DNMT1), the method comprising the steps of:
 (i) measuring kinetic isotope effects on the DNMT1-catalyzed methylation of hemimethylated DNA to obtain the DNMT1 transition state structure,   wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
         (ii) determining the molecular electrostatic potential at the van der Waals surface computed from a wave function of the DNMT1 transition state and a geometric atomic volume of the DNMT1 transition state; 
         (iii) obtaining a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state; and 
         (iv) testing the compound for inhibitory activity to DNMT1 by determining if the compound inhibits DNMT1-catalyzed methylation of hemimethylated DNA; 
         wherein a compound that inhibits DNMT1-catalyzed methylation of hemimethylated DNA is an inhibitor of DNMT1; 
         thereby detecting, screening for or designing an inhibitor of human DNA methyltransferase 1 (DNMT1). 
       
     
     
         3 . A system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon which, when executed by the one or more data processing apparatus, cause the one or more data processing apparatus to perform a method comprising:
 (i) using experimental kinetic isotope effects and quantum chemical analysis on human DNA methyltransferase 1 (DNMT1)-catalyzed methylation of hemimethylated DNA to obtain the DNMT1 transition state structure,   wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
         (ii) calculating a molecular electrostatic potential at a van der Waals surface computed from a wave function of the DNMT1 transition state and a geometric atomic volume of the DNMT1 transition state; and 
         (iii) identifying in silico from a library of compounds a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state; 
         wherein the chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state is a putative inhibitor of DNMT1. 
       
     
     
         4 . A system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon which, when executed by the one or more data processing apparatus, cause the one or more data processing apparatus to perform a method comprising:
 (i) determining a molecular electrostatic potential at the van der Waals surface computed from a wave function of a human DNA methyltransferase 1 (DNMT1) transition state and a geometric atomic volume of the DNMT1 transition state, wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
       
       and
 (ii) designing a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state; 
 wherein a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state is a putative inhibitor of DNMT1. 
 
     
     
         5 . A computer-implemented method performed using a system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon, the methods comprising:
 (i) using kinetic isotope effects on human DNA methyltransferase 1 (DNMT1)-catalyzed methylation of hemimethylated DNA to obtain the DNMT1 transition state structure,   wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
         (ii) determining a molecular electrostatic potential at the van der Waals surface computed from a wave function of the DNMT1 transition state and a geometric atomic volume of the DNMT1 transition state; and 
         (iii) identifying from a library of compounds a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state; 
         wherein the chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state is a putative inhibitor of DNMT1. 
       
     
     
         6 . A computer implemented method performed using a system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon, the methods comprising:
 (i) determining the molecular electrostatic potential at the van der Waals surface computed from a wave function of a human DNA methyltransferase 1 (DNMT1) transition state and a geometric atomic volume of the DNMT1 transition state, wherein the DNMT1 transition state comprises the structure   
       
         
           
           
               
               
           
         
       
       and
 (ii) designing a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the DNMT1 transition state; 
 wherein a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state is a putative inhibitor of DNMT1. 
 
     
     
         7 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1);
 the method comprising:   (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 1 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.   
     
     
         8 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1); the method comprising:
 (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 2 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.   
     
     
         9 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1);
 the method comprising:   (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 3 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.   
     
     
         10 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1);
 the method comprising:   (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 4 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.   
     
     
         11 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1);
 the method comprising:   (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 5 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.   
     
     
         12 . A method of manufacturing an inhibitor of human DNA methyltransferase 1 (DNMT1);
 the method comprising:   (i) obtaining information regarding the design of a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the DNMT1 transition state and the geometric atomic volume of the DNMT1 transition state according to  claim 6 ;   (ii) synthesizing the compound; and   (iii) optionally testing the compound for inhibitory activity to DNMT1;   to thereby manufacture a compound that is an inhibitor of DNMT1.