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MindMap Gallery Basic principles and methods of new drug research

Basic principles and methods of new drug research

This is a mind map about the basic principles and methods of new drug research, including the relationship between the chemical structure and biological activity of new drugs, the discovery of lead compounds, and the optimization of lead compounds.

Edited at 2023-12-18 22:25:07

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Basic principles and methods of new drug research

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Outline

Basic principles and methods of new drug research

The relationship between chemical structure and biological activity of new drugs

Physicochemical properties and biological activity

Exponential partition coefficient and biological activity

The exponential partition coefficient is the ratio of the concentration of a compound in the organic phase and the aqueous phase when the distribution of the compound in the organic phase and the aqueous phase reaches equilibrium, that is, P=CO/CW, commonly expressed as logP, log P= log(CO/CW)

logP is the sum of the hydrophilicity and hydrophobicity of all functional groups that make up the entire molecule

The larger the P value, the higher the lipophilicity of the drug.

Acidity, alkalinity and biological activity

Most drugs are weak acids or bases, and their degree of dissociation is determined by the dissociation constant pK of the compound and the pH of the solution medium.

Dissociation constant pKa=pH Ig ([RCOOH]/[RCOO-])

After weak acid or weak base drugs are dissociated in body fluids, the ratio of ionic and nonionic (molecular) molecules is determined by the dissociation constant pKa and the pH of the medium.

Drug-receptor interactions and biological activity

According to the way drugs work in the body, drugs are divided into structurally specific drugs and structurally non-specific drugs.

The role of chemical bonds

Chemical bonds are divided into two categories: reversible and irreversible

The covalent binding of drugs to receptors is irreversible, but in most cases, the binding of drugs to receptors is reversible

Reversible bonding methods mainly include ionic bonds, hydrogen bonds, van der Waals forces, etc.

The role of stereochemistry

geometric isomerism

optical isomerism

Conformational isomerism

The role of functional groups

Some specific functional groups in the molecule can change the structure and properties of the entire molecule, thereby affecting the binding of drugs to receptors and their pharmacological activity.

Discovery of lead compounds

Lead compound, also known as prototype compound, has the desired biological or pharmacological activity, but has some other unsuitable properties, such as higher toxicity, other biological activities, poor solubility or drug metabolism issues

Obtain lead compounds from natural products

Using existing drugs as lead compounds

Discover lead compounds based on drug side effects

The sulfonylurea hypoglycemic drug tolbutamide was discovered through structural modification based on the hypoglycemic side effects of sulfonamide drugs.

Discover lead compounds through drug metabolism studies

Use existing breakthrough drugs as lead compounds

Using active endogenous substances as lead compounds

Generate leads using combinatorial chemistry and high-throughput screening

Optimization of lead compounds

There are many methods for the optimization of lead compounds, which can be roughly divided into two categories: traditional medicinal chemistry methods and modern methods.

Use computers to perform targeted screening to obtain leads

bioisosteric replacement

Burger further expanded this definition: Bioisosteres are organisms that have similar molecular shapes and volumes, similar charge distributions, and thus exhibit similar physical properties (such as hydrophobicity) that produce similar or antagonistic effects on the same target. Active molecules or groups.

Bioisosteres can be divided into two categories: classical and non-classical bioisosteres.

Classic bioisosteres include atoms or groups with the same outer shell valence electrons, elements of the same main group in the periodic table, and ring equivalents

Non-classical bioisosteres refer to molecules or groups with similar spatial arrangement, electrical properties or other properties. Substituting each other will produce similar or opposite biological activities.

prodrug design

Prodrugs, also known as prodrugs, prodrugs, prodrugs, etc., refer to drugs that are inactive or less active in vitro after modification of their chemical structure and release activity through enzymatic or non-enzymatic transformation in the body. compounds that exert medicinal effects

Classification

Bioprecursor prodrug: It is a new compound obtained by molecular modification of an active compound. The new compound is a substrate of a metabolic enzyme. The active metabolite produced by enzyme metabolism is the expected active molecule.

The principle of carrier prodrug is to connect the active drug to the carrier through covalent bonds, thereby changing the physical and chemical properties of the drug, and then releasing the active drug under the action of enzymes. Drugs containing alcohol or carboxylic acid groups, the most common form of prodrug is ester;

The purpose of prodrug design

Improve bioavailability and biofilm permeability

Improve drug targeting

Extend drug action time

Improve the water solubility and stability of drugs, overcome bad odor or physical and chemical properties to meet the needs of preparations

Soft drug design

Design drugs that are easily metabolized and inactivated, so that after the drug completes its therapeutic effect, it will decompose, inactivate and be quickly excreted from the body according to a predetermined metabolic pathway and a controllable rate, thereby avoiding the accumulation of toxicity of the drug. This type of drug is called soft drug

Quantitative structure activity relationship

Quantitative structure-activity relationship research is a quantitative analysis of the relationship between the chemical structure of a drug molecule and its biological activity, to find out the quantitative changes between the chemical structure and biological activity of the drug, or to obtain the mathematical equation of the structure-activity relationship, which provides the basis for further structure Optimization provides theoretical basis.

Computer Aided Drug Design

Computer-aided drug design (CADD) uses the computer's fast calculation function, comprehensive logical judgment function, and clear graphical display function to intersect disciplines such as quantum chemistry, molecular mechanics, medicinal chemistry, life sciences, computer graphics, and information science. Fusion, drug design starts from the mechanism of action of drug molecules.