Factorial chemical libraries

Abstract

A method and library for determining the sequence of monomers in a polymer which is complementary to a receptor. The method provides for formation of pooled ( 6 ) and separate ( 10, 12 ) products. Separate products are subjected only to subsequent pooled coupling steps. Each pooled product is subsequently divided for formation of pooled and separate products. The resulting polymer library includes groups of polymer products. A first group of products ( 42 ) is used to identify the monomer at a first location in a polymer that is complementary to a receptor. A second group of products ( 44 ) is used to identify the monomer at a second location in a polymer that is complementary to a receptor.

1 . A polymer library screening kit comprising families of polymers X 3 -X 2p X 1p , X 3p -X 2 -X 1p  and X 3p -X 2p -X 1  wherein: 
 X 3p -X 2p -X 1  comprises a collection of at least first and second polymer mixtures, said first polymer mixture having a first monomer in a first position of polymer molecules therein, and different monomers in second and third positions of said polymer molecules therein, and wherein said second polymer mixture has a second monomer in said first position of polymer molecules therein, and different monomers in second and third positions of said polymer molecules therein;    X 3p -X 2 -X 1p  comprises a collection of at least third and fourth polymer mixtures, said third polymer mixture having a third monomer in said second position and said fourth polymer mixture having a fourth monomer in said second position, each of said third and fourth polymer mixtures having different monomers in said first and third positions; and    X 3 -X 2p -X 1p  comprises a collection of at least fifth and sixth polymer mixtures, said fifth polymer mixture having a fifth monomer in said third position and said sixth polymer mixture having a sixth monomer in said third position, each of said fifth and sixth polymer mixtures having different monomers in said first and second positions, wherein said first, third, and fourth monomers are the same or different and said second, fourth, and fifth monomers are the same or different.    
     
     
         2 . The polymer library as recited in  claim 1  wherein each of said polymer mixtures are selected from the group consisting of mixtures of peptides and mixtures of oligonucleotides.  
     
     
         3 . The polymer library as recited in  claim 1  wherein said polymers comprise at least four monomers.  
     
     
         4 . The polymer library as recited in  claim 1  further comprising labelled receptor molecules, and means for identifying mixtures of said polymers to which said receptor molecules are bound.  
     
     
         5 . The polymer library as recited in  claim 9  wherein said receptor molecules are labelled with a fluorescein label.  
     
     
         6 . The polymer library as recited in  claim 1  wherein said polymers are coupled to a solid substrate.  
     
     
         7 . A method of identifying first and second monomers in a polymer that is complementary to a receptor comprising the steps of: 
 coupling first and second monomers in a first basis set to individual substrates and mixing substrates to form first pooled products;    coupling said first and second monomers from said first basis set to individual substrates, and not mixing said substrates to form at least first and second separate products;    separately coupling first and second monomers from a second basis set to substrates from said first pooled products and not mixing said substrates to form at least third and fourth separate products;    coupling said first and second monomers from said second basis set to individual substrates from said first separate products and mixing said substrates to form second pooled products;    coupling said first and second monomers from said second basis set to individual substrates from said second separate products to form third pooled products; and    exposing a receptor to said third and fourth separate products to identify a second monomer in a polymer which is complementary to a receptor, and exposing said second and third pooled products to said receptor to identify a first monomer in a polymer which is complementary to said receptor.    
     
     
         8 . The method as recited in  claim 7  wherein said step of exposing to a receptor is preceded by the step of performing additional steps of coupling and mixing to said second pooled products and said third pooled products.  
     
     
         9 . The method as recited in  claim 7  further comprising the step of mixing a portion of said third and fourth separate products to form fourth pooled products.  
     
     
         10 . The method as recited in  claim 9  further comprising the step of separately coupling monomers from a third basis set to said fourth pooled products.  
     
     
         11 . The method as recited in  claim 7  wherein said monomers are amino acids.  
     
     
         12 . The method as recited in  claim 7  wherein said monomers are nucleotides.  
     
     
         13 . The method as recited in  claim 7  wherein said steps are repeated to screen polymers having at least three monomers therein.  
     
     
         14 . The method as recited in  claim 7  wherein at least one of said first and second monomers cannot be determined unambiguously, further comprising the steps of: 
 synthesizing an array of polymers, said potential complementary polymers using a light-directed synthesis technique; and    detecting binding of said receptor to said potential complementary polymers.    
     
     
         15 . A library of polymers to be used for identification of a receptor complementary to at least one of said polymers comprising: 
 a first set of polymers, said first set of polymers having a first monomer in a first position, and a plurality of different monomers at a second position; and    a second set of polymers, isolated from said first set of polymers, said second set of polymers having a second monomer in said second position, and a plurality of different monomers in said first position.    
     
     
         16 . A library of polymers as recited in  claim 15  further comprising: 
 a third set of polymers, isolated from said first and second sets of polymers, said third set of polymers having a third monomer in said first position and a plurality of different monomers at said second position.    
     
     
         17 . A library of polymers as recited in  claim 16  further comprising: 
 a fourth set of polymers, isolated from said first, second, and third sets of polymers, said fourth set of polymers having a fourth monomer in said second position and a plurality of different monomers in said first position.