# US 12,763,170 B2 · Method, system, and tool for creating, filtering, and selecting molecules in drug design for therapeutic effects

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- Number: US 12,763,170 B2
- Document ID: US12763170B2
- Status: Granted
- Kind: B2
- Application number: 17/990,703
- Filed: 2022-11-20
- Published: 2024-05-30
- Granted: 2026-10-13
- Earliest claimed: 2022-11-20
- Assignees: United Arab Emirates University
- Applicants: United Arab Emirates Universtiy
- Inventors: Alya A. Arabi; Alaa M. A. Osman
- Web page: https://patentgrep.com/patent/US12763170B2

## CPC

- G16C 10/00: Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like
- G16C 20/50: Molecular design, e.g. of drugs
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE

## Abstract

A system and method for identifying bioisosteres of a molecule are provided. These methods are particularly useful for confirming that amides and 1,2,3-triazoles are bioisosteres of one another. The methods for evaluating bioisosteres of a molecule include selecting a first molecule of interest having an amide group as a first bioisostere, replacing the amide group with a 1,2,3-triazole group as a second bioisostere to obtain a second molecule, completing a quantum mechanics (QM) simulation for each molecule, calculating average electron density (AED) values corresponding to the first and second bioisosteres in the first and second molecules, respectively, and confirming the bioisosterism based on the calculated AED values of the biosiosteres. These methods can be further used to identify further bioisosteres thereof. The present methods and systems can be used to aid in many applications including but not limited to the development of drug design.

## Claims

### Claim 1

A method for discovering new bioisosteres of a molecule, the method comprising:
selecting a first molecule of interest having an amide group as a first bioisostere;
replacing the amide group of the first molecule of interest with a 1,4-substituted or 1,5-substituted 1,2,3-triazole group as a second bioisostere to obtain a second molecule with the second bioisostere;
completing quantum mechanics (QM) simulations to obtain optimized geometries having no imaginary frequencies for the first and second molecules containing the first and second bioisosteres as docked in a receptor or as not docked in a receptor;
evaluating average electron density (AED) values, using an average electron density tool, corresponding to the first and second bioisosteres in the first and second molecules as docked in the receptor;
confirming experimentally observed bioisosterism between the 1,4-substituted or 1,5-substituted 1,2,3-triazole group and the amide group based on the calculated AED values;
identifying those calculated AED values equivalent between the first and second bioisostere, wherein the equivalent calculated AED values have a difference of no more than 10% between one another;
identifying additional sets of atoms having calculated AED values corresponding to the calculated AED values equivalent between the first and second bioisosteres, wherein the corresponding calculated AED values have a difference of no more than 10% from the equivalent calculated AED value of the first bioisostere;
computationally replacing the amide group of the first molecule of interest with one of the identified additional sets of atoms to obtain a third molecule with a third bioisostere; and
screening the third molecule with the third bioisostere to determine whether the third molecule with the third bioisostere is a drug candidate having a desired biological activity.

### Claim 2 (depends on 1)

The method of claim 1, wherein the screened third molecule with the third bioisostere is further evaluated to determine any commonalities in biological activity to the first molecule of interest having the first bioisostere.

### Claim 3 (depends on 1)

The method of claim 1, wherein the screened third molecule with the third bioisostere shares common biological activity with the first molecule of interest having the first bioisostere.

### Claim 4 (depends on 1)

The method of claim 1, wherein each bioisostere is considered in any isomeric form of the respective bioisostere.

### Claim 5 (depends on 1)

The method of claim 1, wherein the calculated average electron density (AED) values are calculated as a sum of electron population divided by a sum of volumes of all atoms in the first or second bioisostere, wherein the electron population and the volumes of all atoms in the first or second bioisostere are obtained using quantum simulations.

### Claim 6 (depends on 1)

The method of claim 1, wherein the screening of the third molecule with the third bioisostere comprises screening for new bioisosteres of the first molecule having one or more uses selected from the group consisting of:
1) identifying, generating, discovering, and creating new bioisosteres containing the additional sets of atoms having a desired biological activity for treating a specific disease;
2) identifying, generating, discovering, designing, and creating new molecules having a desired biological activity common to a biological activity of the first molecule;
3) filtering, identifying, and selecting molecules having a desired therapeutic effect to aid in drug design;
4) determining commonalities in biological activity between the first molecule and the third molecule, wherein when such commonalities in biological activity between the first molecule and the third molecule are found, further investigating the third molecule as a pharmaceutical of interest;
5) refining and improving one or more pharmacokinetic and pharmacodynamic properties of the first molecule selected from the group consisting of reducing sides effects, reducing toxicity, increasing half-life, improving an ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile, improving solubility, improving stability, changing bond strength, varying rate of excretion to reduce damages, improving potency, increasing selectivity, and a combination thereof by replacing the first bioisostere of the first molecule with the additional set of atoms having a calculated AED values being within 90% or more of the AED of the first bioisostere;
6) providing an advancement in technology over existing software used in drug design and drug discovery;
7) reducing a number of molecules for further experimental testing;
8) saving time and money by providing a reduced number of hit candidates potentially having the desired biological activity; and
9) a combination thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein an AED value of the simulated third molecule is identified according to a method comprising:
completing a QM simulation for the third molecule;
partitioning the third molecule into atoms;
delimiting the partitioned atoms by zero-flux surfaces to obtain interatomic basins;
delimiting an outer limit of the atomic basins with three different isodensity envelopes;
obtaining atomic basins and performing atomic integrations on the partitioned atoms of the third molecule;
extracting data for each of the partitioned atoms in the third molecule;
segregating a bioisosteric group of the third molecule from other atoms in the third molecule; and
calculating AED values of the bioisosteric group of the third molecule.

### Claim 8 (depends on 1)

The method of claim 1, wherein the additional sets of atoms having the corresponding calculated AED values having a difference of no more than 10% of the equivalent calculated AED value of the first bioisostere are identified according to a method comprising:
determining a first additional set of atoms;
replacing the set of atoms of the first molecule of interest with the first additional set of atoms to obtain one or more isomeric forms of a first potential candidate molecule;
completing a QM simulation for the first potential candidate molecule;
partitioning the first potential candidate molecule into atoms;
delimiting the partitioned atoms by zero-flux surfaces to obtain interatomic basins;
delimiting an outer limit of the atomic basins with three different isodensity envelopes;
obtaining atomic basins and performing atomic integrations on the partitioned atoms of the first potential candidate molecule;
extracting data for each of the partitioned atoms in the first potential candidate molecule;
segregating the first additional set of atoms of the first potential candidate molecule from other atoms in the first potential candidate molecule;
calculating AED values of the first additional set of atoms of the first potential candidate molecule;
confirming that the AED values of the first additional set of atoms of the first potential candidate molecule and the AED values corresponding to the first bioisostere in the first molecule are different from one another by no more than a predetermined 10%; and
repeating these steps for one or more further additional set of atoms of each of one or more further potential candidate molecule until one or more potential candidate molecules, including the first potential candidate molecule, having identified additional sets of atoms having calculated AED values different by no more than a predetermined 10% of the calculated AED values of the first bioisostere is obtained.

### Claim 9 (depends on 8)

The method of claim 8, wherein the calculated AED values of the first bioisostere and each of the additional sets of atoms are equivalent to one another, irrespective of any groups to which the first bioisostere and each of the additional sets of atoms are attached.

### Claim 10 (depends on 8)

The method of claim 8, wherein the calculated AED values of the first bioisostere and each of the additional sets of atoms have capping groups.

### Claim 11 (depends on 8)

The method of claim 8, wherein the step of completing a QM simulation for the first potential candidate molecule and each of the further potential candidate molecules optimizes the geometries, computes the frequency, and generates a wavefunction from which volumes and electron densities are extracted.