Patent ID: 6210900
Filing Date: 2001-04-03
Classification: B01J,C40B,G01N

Abstract:
A method of developing a structure activity relationship of essential moieties for a lead structure from a series of essentially the same combinatorial library prepared repeatedly from substantially the same specified set of reaction sequences to form a series of similar combinatorial libraries, which comprises:a) preparing a first combinatorial library of the lead structure, wherein each reaction choice in the first registry is encoded, byi) sorting tagged beads into containers according to the number of reaction choices in the first registry, wherein the beads within each container are similarly tagged and each container contains uniquely tagged beads;ii) adding specified reagents under specified conditions to each container to complete the first registry;iii) combining all of the reacted beads into a single mixture and then separating the beads into containers according to the number of reaction choices in the next registry;iv) adding specified reagents under specified conditions to each container to complete the next registry;v) repeating steps iii) and iv) until the desired number of registries is obtained; andvi) optionally, combining the beads from the final registry into a single mixture;b) preparing a second combinatorial library of the lead structure, wherein each choice in the second registry is encoded, byi) combining beads tagged similarly to those of a)-i) into a single mixture and then separating the beads into containers according to the number of reaction choices in the first registry;ii) adding specified reagents under specified conditions substantially according to the reaction choices in a)-ii) to each corresponding container to complete the first registry;iii) combining all of the reacted beads into a single mixture and then sorting the beads by flow cytometry into containers substantially according to the number of reaction choices in a)-iii), wherein the beads within each container are similarly tagged and each container contains uniquely tagged beads;iv) adding specified reagents under specified conditions to each container substantially according to the reaction choices in a)-iv) to each corresponding container to complete the second registry;v) repeating step a)-v) substantially according to the reaction choices of the corresponding registry in the first library until a number of registries corresponding to the first library is obtained; andvi) optionally, combining the beads from the final registry into a single mixture;c) preparing subsequent libraries of the lead structure according the procedure in b) except that the sort step is performed prior to a different registry in each subsequent library, so that the number of libraries is substantially equal to the number of registries; andd) developing a structure activity relationship based on a population analysis of each combinatorial library, byi) contacting the library components with a pharmaceutical target;ii) identifying beads containing active molecules by their encoded registry; andiii) determining the populations of active structures.