Methods for determining relative binding energy of monomers and methods of using the same

Patent metadata

Field	Value
Publication number	US-2016299157-A1
Application number	US-201615188214-A
Country	US
Kind code	A1
Filing date	Jun 21, 2016
Priority date	May 21, 2014
Publication date	Oct 13, 2016
Grant date	—

Abstract

Disclosed herein are monomers that exhibit reduced estradiol related receptor binding activity, and methods for identifying monomers that exhibit reduced estradiol related receptor binding activity. Methods for preparing a polymeric composition using such monomers are also disclosed. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

First claim

What is claimed is:

1 . A method for preparing a polymeric composition, the method comprising:
a) determining a first binding energy of an ortho substituted phenolic monomer in a ligand binding domain cavity of an estradiol related receptor comprising ERR-α or ERR-β, b) determining a second binding energy of the corresponding unsubstituted phenolic reference monomer in the same ligand binding domain cavity of an estradiol related receptor comprising ERR-α or ERR-β; c) determining the relative binding energy based on the first binding energy and second binding energy; and d) reacting the ortho substituted phenolic monomer under conditions effective to provide a polymeric composition including polycarbonate if the ortho substituted phenolic monomer exhibits a relative binding energy in the range of from 2.7 kcal/mol to 14 kcal/mol or an intra-molecular hydrogen bond range of from about 1.7 Å to about 2.1 Å, wherein the ortho substituted phenolic monomer and the polymeric composition do not exhibit a half maximal inhibitory concentration (IC 50 ) less than 0.00025M for alpha or beta in vitro estradiol receptors.

2 . The method of claim 1 , wherein the ortho substituted phenolic monomer has at least one oxygenated substituent in an ortho position of a phenolic group of the phenolic monomer.

3 . The method of claim 2 , wherein the ortho substituted phenolic monomer is an ortho alkoxy or ortho acid substituted phenolic monomer.

4 . The method of claim 1 , wherein the ortho substituted phenolic monomer has at least one oxygenated substituent in an ortho position of a phenolic group of the phenolic monomer, the oxygenated ortho substituent comprising a structure —OR″, —COOR (carboxylic acid or ester), —O—C(O)R (carboxylate), —O—C(O)—OR (carbonate), or —C(O)—R (aldehyde or ketone), wherein R is an H, C1-18 alkyl, C6-18-aryl, or C7-18-alkylaryl group and wherein —OR″ is a C1-18 alkyl, C6-18-aryl, or C7-18-alkylaryl alkoxide;

5 . The method of claim 1 , wherein the estradiol related receptor is ERR-α.

6 . The method of claim 1 , wherein the ortho substituted phenolic monomer is a bisphenol monomer.

7 . The method of claim 1 , wherein the polymeric composition is a polycarbonate.

8 . The method of claim 1 , wherein the ortho substituted phenolic monomer comprises at least one oxygenated substituent ortho to the phenolic hydroxyl group, the oxygenated ortho substituent comprising an alkoxy or carboxylic acid.

9 . The method of claim 8 , wherein an intra-molecular hydrogen bond length of the ortho substituted phenolic monomer is in a range of from about 1.7 to about 2.1 Å, and wherein the intra-molecular hydrogen bond length is the distance between the H of the phenolic hydroxyl group and an oxygen of the alkoxy or carbonyl oxygen of the oxygenated substituent attached in the ortho position of the hydroxyl group.

10 . The method of claim 1 , wherein the binding energy value is determined using the formula: binding energy=energy (complex)−[energy(cavity)+energy(monomer)], wherein energy (complex) is the electronic energy of the phenolic monomer structure in the constrained structure of the ligand binding domain cavity of the estradiol related receptor, the energy(cavity) is the electronic energy of the cavity and the energy(monomer) is the electronic energy of the phenolic monomer.

11 . A method for preparing a polymeric composition, the method comprising:
a) determining a first binding energy of an alkoxy or acid ortho substituted phenolic monomer in a ligand binding domain cavity of an estradiol related receptor comprising ERR-α or ERR-β; b) determining a second binding energy of the corresponding unsubstituted reference phenolic monomer in the same ligand binding domain cavity of an estradiol related receptor comprising ERR-α or ERR-β; c) determining the relative binding energy based on the first binding energy and second binding energy; and d) in response to the alkoxy or acid ortho substituted phenolic monomer exhibiting a relative binding energy in the range of from 2.7 kcal/mol to 14 kcal/mol or an intra-molecular hydrogen bond range of from about 1.7 Å to about 2.1 Å, reacting the alkoxy or acid substituted phenolic monomer under conditions effective to provide a polymeric composition, wherein the alkoxy or acid substituted phenolic monomer and polymeric composition does not exhibit a half maximal inhibitory concentration (IC 50 ) less than 0.00025M alpha or beta in vitro estradiol receptors.

12 . The method of claim 11 , wherein the phenolic monomer having at least one oxygenated substituent in an ortho position of a phenolic group of the phenolic monomer, the oxygenated ortho substituent comprising a structure —OR″, —COOR (carboxylic acid or ester), —O—C(O)R (carboxylate), —O—C(O)—OR (carbonate), or —C(O)—R (aldehyde or ketone), wherein R is an H, C1-18 alkyl, C6-18-aryl, or C7-18-alkylaryl group and wherein —OR″ is a C1-18 alkyl, C6-18-aryl, or C7-18-alkylaryl alkoxide;

13 . The method of claim 11 , wherein the estradiol related receptor is ERR-α.

14 . The method of claim 11 , wherein the phenolic monomer is a bisphenol monomer.

15 . The method of claim 11 , wherein the polymeric composition is a polycarbonate.

16 . The method of claim 11 , wherein the phenolic monomer comprises at least oxygenated substituent ortho to the phenolic hydroxyl group, the oxygenated ortho substituent comprising an alkoxy or carboxylic acid.

17 . The method of claim 16 , wherein an intra-molecular hydrogen bond length of the phenolic monomer is in a range of from about 1.7 to about 2.1 Å, and wherein the intra-molecular hydrogen bond length is the distance between the H of the phenolic hydroxyl group and an oxygen of the alkoxy or carbonyl oxygen of the oxygenated substituent attached in the ortho position of the hydroxyl group.

18 . The method of claim 11 , wherein the binding energy value is determined using the formula: binding energy=energy (complex)−[energy(cavity)+energy(monomer)], wherein energy (complex) is the electronic energy of the phenolic monomer structure in the constrained structure of the ligand binding domain cavity of the estradiol related receptor, the energy(cavity) is the electronic energy of the cavity and the energy(monomer) is the electronic energy of the phenolic monomer.

Assignees

• Sabic Global Technologies Bv

Inventors

• Shetty Sharankumar G
• Kamps Jan Henk
• Chandra Girish
• Tanwar Akhilesh
• Gallucci Robert R
• Ganapathy Bhotla Venkata Ramanarayanan
• Nesakumar Edward J
• Kumar Minor Senthil

Classifications

• C08G64/20 Primary

  General preparatory processes · CPC title

• G06F19/701

  Physics · mapped topic

• G01N33/743 Primary

  Steroid hormones · CPC title

• G01N2333/70567

  Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors · CPC title

• G16B20/30

  Detection of binding sites or motifs · CPC title