# US 5,705,335 A · Design of drugs involving receptor-ligand-DNA interactions

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- Number: US 5,705,335 A
- Document ID: US5705335A
- Status: Granted
- Kind: A
- Application number: 08/369,779
- Filed: 1994-11-28
- Granted: 1998-01-06
- Earliest claimed: 1993-11-26
- Inventors: Lawrence B. Hendry
- Web page: https://patentgrep.com/patent/US5705335A

## CPC

- C12Q 1/6811: Selection methods for production or design of target specific oligonucleotides or binding molecules
- G16B 15/00: ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment
- G16B 15/30: Drug targeting using structural data; Docking or binding prediction
- G16C 20/50: Molecular design, e.g. of drugs
- G16C 20/64: Screening of libraries
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE

## Abstract

It has been discovered that the degree of hormonal activity of candidate ligands correlates better with degree of fit into DNA than with the strength of receptor binding, and that the receptors in the steroid/thyroid hormone/vitamin A and D family alter the physiochemical properties of DNA and in concert with other transcription factors facilitate insertion of the ligand into DNA. As a result, the magnitude of the response is a function of the structure of the ligand as it related to insertion and fit into the DNA and the specificity of the response is a function of the stereochemistry of the receptor through binding to both the ligand and to the DNA. Based on these discoveries, a method is described herein for identifying drugs having increased activity as compared with the natural ligand for receptors such as the estrogenic receptors.

## Claims

### Claim 1

A computer-based method for creating a pharmacophore comprising the computer implemented steps of:
determining the optimal fit of a plurality of compounds having the same or similar biological activity into nucleic acid sequences such that the lowest energy of interaction and best steric fit are obtained;
aligning the compounds relative to the heteroatoms on the nucleic acids;
defining a three dimensional shape as a pharmacophore representing the aggregate average shape resulting from said alignment of the compounds; and
displaying the pharmacophore on a computer screen or in a computer printout.

### Claim 2 (depends on 1)

The method of claim 1, wherein the nucleic acid sequence is selected from the group consisting of deoxyribonucleic acid, double stranded deoxyribonucleic acid, ribonucleic acid, complexes of deoxyribonucleic acid and ribonucleic acid, and apurinic and apyrimidinic sites.

### Claim 3 (depends on 1)

The method of claim 1, wherein the nucleic acid is deoxyribonucleic acid.

### Claim 4 (depends on 1)

A computer-based method for screening a molecule for biological activity wherein the molecule is examined for the ability to fit into the pharmacophore of claim 1 comprising the computer implemented steps of:
measuring the energy of interaction when the molecule is fitted into the pharmacophore;
comparing the energy of interaction of the molecule to a predetermined energy of interaction that correlates to the biological activity; and
displaying the comparison of a computer screen or in a computer printout.

### Claim 5 (depends on 4)

The method of claim 4, wherein the pharmacophore is selected from the group consisting of an estrogen pharmacophore, an antiestrogen pharmacophore, an androgen pharmacophore, a thyroid hormone pharmacophore, and a toxicity pharmacophore.

### Claim 6 (depends on 1)

A computer-based method for screening a molecule for toxic biological activity wherein the molecule is examined for the ability to fit into the pharmacophore of claim 1 comprising the computer implemented steps of:
measuring the energy of interaction when the molecule is fitted into the pharmacophore;
comparing the energy of interaction of the molecule to a predetermined energy of interaction that corralates to the toxic biological activity; and
displaying the comparison on a computer screen or in a computer printout.

### Claim 7 (depends on 1)

A computer-based method for designing a molecule with a desired biological activity comprising the computer implemented steps of:
determining a structure of a molecule which will have a minimal predetermined energy of interaction when fitted into the pharmacophore of claim 1 with the desired biological activity; and
displaying the structure of the molecule on a computer screen or in a computer printout.

### Claim 8 (depends on 1)

The method of claim 1, wherein the biological activity is selected from the group consisting of estrogenic activity, antiestrogenic activity, androgenic activity, thyroid hormone activity, and toxic biological activity.

### Claim 9 (depends on 8)

The method of claim 8, wherein the estrogenic activity is uterotropic activity.

### Claim 10 (depends on 7)

The method of claim 7, wherein the biological activity is selected from the group consisting of estrogenic activity, antiestrogenic activity, androgenic activity, thyroid hormone activity, and toxic biological activity.

### Claim 11 (depends on 6)

The method of claim 6, wherein the pharmacophore is a toxicity pharmacophore.

### Claim 12 (depends on 7)

The method of claim 7, wherein the pharmacophore is selected from the group consisting of an estrogen pharmacophore, an antiestrogen pharmacophore, an androgen pharmacophore, a thyroid hormone pharmacophore, and a toxicity pharmacophore.

### Claim 13 (depends on 4)

The method of claim 4, further comprising:
quantitating the fit of the molecule into the pharmacophore by measuring an amount of volume of the molecule which is placed within the pharmacophore; and
normalizing the amount to an amount of volume of a natural hormone placed within the pharmacophore.

### Claim 14 (depends on 4)

The method of claim 4, further comprising:
quantitating values of electrostatic interactions of the molecule with dummy atoms in the pharmacophore;
optimizing the values of the electrostatic interactions of the molecule with dummy atoms in the pharmacophore; and
normalizing the values of the electrostatic interactions of the molecule to the values for the electrostatic interactions of a natural hormone for the dummy atoms in the pharmacophore.

### Claim 15 (depends on 14)

The method of claim 14, further comprising:
adding the normalized value for the electrostatic interactions of the molecule in the pharmacophore to the normalized value for the volume of the molecule in the pharmacophore.