Columbia University

Cold Spring Harbor Laboratory

Other

The Rockefeller University

W Clark Still

Lawrence Wayne Dillard

Michael H Wigler

John C Reader

Michael H Ohlmeyer

Ge Li

Jong-In Hong

Julian A Simon

Shripad S Bhagwat

Gabriela Chiosis

Philip R Hamann

Michael H J Ohlmeyer

Ivo Boneca

Helma Wennemers

Frank Guarnieri

Seung S Yoon

Shawn D Erickson

Hanoch Senderowitz

Quentin McDonald

Libraries of synthetic receptors are disclosed. The receptors include a polyfunctional organic template which is covalently linked to two or more oligomers. The oligomers may be the same or different and may be straight chain, cyclic or branched. The template may be linked to an identifier which is unique to each synthetic receptor. Although the identifier may be directly attached to the template, it is more common and preferable that the template be covalently linked to a solid support which is itself linked to the identifier. Methods of preparing synthetic receptors and libraries of synthetic receptors are also disclosed as are methods for assaying the libraries to determine which receptors have various desirable characteristics. Among the desirable characteristics are (a) the ability to bind an acceptor molecule; (b) biological activity; (c) the ability to catalyze or inhibit a reaction and (d) potential utility for separating compounds in chromatography.

Synthetic receptors, libraries and uses thereof

The present invention relates to pyrrolidine compounds of the general structure:where n is an integer 1-6 and R is hydrogen or a Cto Cstraight chain or branched alkyl group, and wherein when n=1, R=CHor H, useful for re-sensitizing vancomycin resistant Gram-positive bacteria in which resistance results from the conversion of an amide bond to an ester bond on the cell wall peptide precursors of the bacteria.

Method of re-sensitizing vancomycin resistant bacteria which selectively cleave a cell wall depsipeptide

Encoded combinatorial chemistry is provided, where sequential synthetic schemes are recorded using organic molecules, which define choice of reactant, and stage, as the same or different bit of information. Various products can be produced in the multi-stage synthesis, such as oligomers and synthetic non-repetitive organic molecules. Conveniently, nested families of compounds can be employed as identifiers, where number and/or position of a substituent define the choice. Alternatively, detectable functionalities may be employed, such as radioisotopes, fluorescers, halogens, and the like, where presence and ratios of two different groups can be used to define stage or choice. Particularly, pluralities of identifiers may be used to provide a binary or higher code, so as to define a plurality of choices with only a few detachable tags. The particles may be screened for a characteristic of interest, particularly binding affinity, where the products may be detachable from the particle or retained on the particle. The reaction history of the particles which are positive for the characteristic can be determined by the release of the tags and analysis to define the reaction history of the particle.

Complex combinatorial chemical libraries encoded with tags

The invention is directed to synthetic receptor(s) which comprises a polyfunctional organic template covalently linked to two or more oligomers which may independently be the same or different and may independently be straight chain, cyclic or branched. The template may be linked to an identifier which uniquely defines the synthetic receptor. The identifier is a stable chemical molecule or a plurality of stable chemical molecules distinguishable and detectable to picomolar levels or may be an oligonucleotide. In a preferred embodiment, the template is covalently linked to a solid support which is linked to an identifier. In addition, the invention includes methods of preparing synthetic receptors and synthetic receptor libraries. The synthetic library may be linked with identifiers such that the library comprises a plurality of different synthetic receptor members. The invention also provides methods for assaying a synthetic receptor library to determine suitable synthetic receptor(s) which (a) bind an acceptor molecule; (b) exhibit biological activity; (c) which catalyze a reaction or inhibit a catalyzed reaction; and (d) separate compounds in chromatography.

Synthetic receptors

The present invention relates a method for re-sensitizing vancomycin resistant Gram-positive bacteria in which resistance results from the conversion of an amide bond to an ester bond in the cell wall peptide precursors of the bacteria which comprises using an antibacterial amount of vancomycin or a homolog of vancomycin and an amount of an agent effective to selectively cleave the ester bond so as to thereby re-sensitize vancomycin resistant bacteria.

Method for re-sensitizing vancomycin resistant bacteria which selectively cleave a cell wall depsipeptide

The present invention provides for a method for selecting a molecule for a population which comprises: a) selecting a first molecule with a conformation characterized by a particular set of coordinates that define the position of each atom in the first molecule; b) determining the energy of the first molecule; c) transforming the coordinates of the first molecule to the coordinates of a second structurally distinct molecule to produce a particular conformation of the second molecule characterized by a particular set of coordinates that define the position of each atom in the second molecule; d) determining the energy of the second molecule; thus, selecting either the first molecule or the second molecule for the population based on their relative energies. The selected molecule may be redefined as the first molecule and the procedure repeated iteratively so as to obtain a population of first molecules and a population of second molecules. Based on the populations, the free energy difference between the first molecule and the second molecule may be determined.

Method for determining relative energies of two or more different molecules

Encoded combinatorial chemistry is provided, where sequential synthetic schemes are recorded using organic molecules, which define choice of reactant, and stage, as the same or different bit of information. Various products can be produced in the multi-stage synthesis, such as oligomers and synthetic non-repetitive organic molecules. Conveniently, nested families of compounds can be employed as identifiers, where number and/or position of a substituent define the choice. Alternatively, detectable functionalities may be employed, such as radioisotopes, fluorescers, halogens, and the like, where presence and ratios of two different groups can be used to define stage or choice. Particularly, pluralities of identifiers may be used to provide a binary or higher code, so as to define a plurality of choices with only a few detachable tags. The particles may be screened for a characteristic of interest, particularly binding affinity, where the products may be detached from the particle or retained on the particle. The reaction history of the particles which are positive for the characteristic can be determined by the release of the tags and analysis to define the reaction history of the particle.

Supports and combinatorial chemical libraries thereof encoded by

Methods for recording the reaction history of a solid support

The invention is directed to synthetic receptor(s) which comprises a polyfunctional organic template covalently linked to two or more oligomers which may independently be the same or different and may independently be straight chain or branched. The template may be linked to an identifier which uniquely defines the synthetic receptor. The identifier is a stable chemical molecule or a plurality of stable chemical molecules distinguishable and detectable to picomolar levels or may be an oligonucleotide. In an preferred embodiment, the template is covalently linked to a solid support which is linked to an identifier.

Methods of determining the structure of a compound encoded by

The invention is directed to a method for generating possible conformations of a molecule comprising the steps of:

Rapidly convergent method for boltzmann-weighted ensemble generation in

The subject invention provides chiral receptor molecules having the structure: ##STR1## wherein A has the structure: ##STR2## and R.sub.1 and R.sub.2 are independently the same or different and are H, F, alkyl, aryl, etc.; X is CH.sub.2 or NH; Y is C.dbd.O or SO.sub.2 ; and n is 0 to about 3; which are useful for the purification of enantiomers of amino acid derivatives and other compounds. The subject invention also provides methods of preparing said receptor molecules.

A.sub.4 B.sub.6 macrotricyclic enantioselective receptors for amino acid

The present invention relates to a composition having the general formula: ##STR1## wherein each of A, B, C, X, Y, and Z is independently O, NH, N(CH.sub.2).sub.m CH.sub.3, N(C.dbd.O) (CH.sub.2).sub.m CH.sub.3, CH.sub.2, S, or Se; each of R.sub.1, R.sub.2, and R.sub.3 is independently phenyl, 4-hydroxyphenyl, pyridyl, pyrrolyl, indolyl, naphthyl, thiophenyl, (C.dbd.O) (CH.sub.2).sub.p CH.sub.3, NH(C.dbd.O) (CH.sub.2).sub.p CH.sub.3, OH, COOH, NH.sub.2, or SH; and m, n, and p are integers between 0 and 5. The composition is a chiral receptor molecule useful for the purification of enantiomers of derivatives of amino acids and of compounds able to form hydrogen bonds. The preparation of the composition involves coupling a trifunctional aromatic molecule with three protected chiral molecules at the three aromatic groups, cleaving protecting groups, and joining adjacent chiral groups by multiple lactamizations. The receptor may be used in a form either bound to a solid support or dissolved in an immiscible phase to effect convenient purification of enantiomers or other compounds of interest.

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New York, NY, United States of America

W Clark Still