Method for predicting ADMET properties using Abbreviated Profile of Drugs (A-POD)

Abstract

A novel numerical and graphical representation has been developed to better comprehend the physicochemical, biological and pharmacokinetic properties of drug-like compounds. Abbreviated profile of drug (A-POD) would help in considering and visualizing the various compound characteristics as one entity. The salient features of A-POD are: a unique way of representing the compound properties, computer friendly numerical string representation making comparison of any properties possible, graphical representation that gives a snapshot of properties and their relative changes, and its usefulness in qualitatively predicting the ADMET properties based on chemical properties alone. This simple yet powerful web-based tool is especially useful in comparing any two compounds at one time. A new therapeutic agent can be compared with the reference compound quickly and easily, by checking which properties are affected and finding out whether it possesses better drug-like properties. Keywords: Drug discovery, Pharmacokinetics, in-silico ADMET, Drug-like properties, ADMET prediction, Profile of drugs, A-POD

What I claim as my invention is: 
     
         1 . A computer-implemented method for predicting the pharmacokinetic properties of a compound based on its chemical properties and providing a comprehensive abbreviated profile of a drug compound in a numerical representation to aid in drug design, said method comprising steps of:
 (i) defining a set of chemical property parameters, wherein the set comprises molecular weight (W), hydrogen-bond acceptors (R), hydrogen-bond donors (G), octanol-water partition coefficient (L), and comprehensive polar surface area (S);   (ii) defining a set of biological property parameters, wherein the set comprises biological activity (B);   (iii) defining a set of pharmacokinetic property parameters, wherein the set comprises absorption (A), distribution (D), metabolism (M), excretion (E), and toxicity (T), and setting the pharmacokinetic or ADMET rules based on the favorable and unfavorable dependencies on chemical property parameters;   (iv) obtaining, for one or more drug compounds, values associated with each of the property parameters and setting an upper and lower limit for each of said values;   (v) determining, for one or more drug compounds, a set of normalized values for each property parameter by dividing the values associated with each of the property parameters by its upper limit and multiplying the resulting number by ten;   (vi) determining, for one or more drug compounds, a set of abbreviated profile of drug compound (A-POD) values associated with each of the property parameters by rounding off the normalized values to the lowest integer, wherein the integers are between 0 and 9;   (vii) determining, for one or more drug compounds, a set of abbreviated profile of drug compound (A-POD) values associated with each of the pharmacokinetic property parameters based on the chemical A-POD values using the ADMET rules and rounding off the values to the highest integer, wherein the integers are between 0 and 9;   (viii) generating, for one or more drug compounds, a numerical representation of the comprehensive A-POD values associated with each of the property parameters defined as CA-POD (X:WRGLSBADMET), wherein X represents the name of the drug, wherein W corresponds to the A-POD value associated with molecular weight; R corresponds to the A-POD value associated with hydrogen-bond acceptors; G corresponds to the A-POD value associated with hydrogen-bond donors; L corresponds to the A-POD value associated with octanol-water partition coefficient; S corresponds to the A-POD value associated with comprehensive polar surface area; B corresponds to the A-POD value associated with biological activity; A corresponds to the A-POD value associated with absorption; D corresponds to the A-POD value associated with distribution; M corresponds to the A-POD value associated with metabolism; E corresponds to the A-POD value associated with excretion; and T corresponds to the A-POD value associated with toxicity;   (ix) displaying, for one or more drug compounds, the numerical representation of said A-POD values on a two-dimensional graph, wherein the A-POD values are displayed on the y-axis and the property parameters are displayed on the x-axis;   wherein steps (i)-(ix) are performed on a suitably programmed computer.   
     
     
         2 . The method of  claim 1  further comprising: repeating steps (i) through (ix) using two different drug compounds, determining differences between the A-POD values associated with each of the property parameters for the two different drug compounds, and displaying the differences on a two-dimensional graph, wherein the differences between the A-POD values are displayed on the y-axis and the property parameters are displayed on the x-axis. 
     
     
         3 . The method of  claim 1  wherein the A-POD value for biological property parameter (B) in micromolar range is determined by taking ten thousand minus biological activity and dividing by ten thousand and then multiplying the resulting number by five and finally adding zero. 
     
     
         4 . The method of  claim 1  wherein the A-POD value for biological property parameter (B) in nanomolar range is determined by taking one thousand minus biological activity and dividing by one thousand and then multiplying the resulting number by five and finally adding five. 
     
     
         5 . The method of  claim 1  wherein the ADMET rule for absorption (A) is based on favorable chemical properties octanol-water partition coefficient (L) and comprehensive polar surface area (S) and unfavorable chemical property molecular weight (W). 
     
     
         6 . The method of  claim 5  wherein the absorption (A) is determined using A-POD values by adding octanol-water partition coefficient (L) and comprehensive polar surface area (S) and subtracting molecular weight (W) and dividing the resulting number by three. 
     
     
         7 . The method of  claim 1  wherein the ADMET rule for distribution (D) is based on favorable chemical properties octanol-water partition coefficient (L) and comprehensive polar surface area (S). 
     
     
         8 . The method of  claim 7  wherein the distribution (D) is determined using A-POD values by adding octanol-water partition coefficient (L) and comprehensive polar surface area (S) and dividing the resulting number by two. 
     
     
         9 . The method of  claim 1  wherein the ADMET rule for metabolism (M) is based on favorable chemical property octanol-water partition coefficient (L). 
     
     
         10 . The method of  claim 9  wherein the metabolism (M) is determined using A-POD values by taking octanol-water partition coefficient (L) and dividing the resulting number by one. 
     
     
         11 . The method of  claim 1  wherein the ADMET rule for excretion (E) is based on favorable chemical properties octanol-water partition coefficient (L) and molecular weight (W). 
     
     
         12 . The method of  claim 11  wherein the excretion (E) is determined using A-POD values by adding octanol-water partition coefficient (L) and comprehensive molecular weight (W) and dividing the resulting number by two. 
     
     
         13 . The method of  claim 1  wherein the ADMET rule for toxicity (T) is based on favorable chemical property octanol-water partition coefficient (L). 
     
     
         14 . The method of  claim 13  wherein the toxicity (T) is determined using A-POD values by taking octanol-water partition coefficient (L) and dividing the resulting number by one. 
     
     
         15 . The method of  claim 1  wherein the ADMET rule for the A-POD value associated with any pharmacokinetic property parameter as a function of A-POD values associated with different chemical property parameters is defined using the weighted mean equation such as:
   Π(Γ)=[Σα N β N Γ N ]/Σβ N =[α 1 β 1 Γ 1 +α 2 β 2 Γ 2 + . . . +α N β N Γ N ]/Σβ N  
 
 
       wherein,
 Π is the A-POD value associated with pharmacokinetic property parameter; 
 Γ is the A-POD value associated with chemical property parameter(s); 
 N is the number of chemical property parameters dependencies; 
 α is the favorability factor, which is plus one when favorable and minus one when unfavorable; 
 β is the weighting factor for chemical property parameter; and 
 Σ is the summation sign. 
 
     
     
         16 . The method of  claim 2  wherein the score based on the differences of A-POD values associated with each of the pharmacokinetic property parameters for the two different drug compounds is an indicator of the progress in the drug design, which is determined by adding difference of A-POD values associated with absorption (A) and distribution (D) and subtracting metabolism (M), excretion (E) and toxicity (T). 
     
     
         17 . The method of  claim 16  wherein the score is assigned a positive sign if the difference of A-POD values associated with biological activity (B) is positive, indicating that the drug design is going in “right” direction as suggested by the trends in the differences of A-POD values associated with the chemical property parameters; the score is assigned a negative sign if the difference of A-POD values associated with biological activity (B) is negative, indicating that the drug design is going in “wrong” direction as suggested by the trends in the differences of A-POD values associated with the chemical property parameters.