drug targets

What is medicine?

1-1 Definition of Drugs
Substances that enter in vivo and have biological effects
ex) Caffeine, nicotine, alcohol can also be a medicine
It should be borne in mind that there are differences in effects for each substance.
It can be poisonous when used at high doses for a long time.

1-2 Good Drug
Drugs exhibiting desired activity and free from toxicity and side effects
Since drugs have latent toxicity, the dose and duration should be carefully determined according to the person.
Rather than aiming for activity, drugs should be developed by focusing on non-toxic, selective toxicity.
Drugs to be developed: Medical need vs economic factor

1-3 Relationship between Drugs and Living Things
Drug - Systemic Circulation - Cell or Target - Functional Change
In modern times, drugs will be developed based on targets.
Traditionally, it has been targeted at a specific cell.

Drug to Cell Pathway(DCP), Drug to Target Pathway(DTP)
Change to the target base because there is a mismatch between cell activity and human activity.
Target selectivity is important, but target identification is difficult.
The diversity of signal pathways cannot be considered.

Pharmacodynamics
Study how drugs bind to the binding site of a target and have pharmacological effects.
Pharmacokinetics (PK)
Study how drugs are absorbed, distributed, metabolized, and excreted (ADME)

1-4 Classification of Drugs
Classification according to chemical structure: If you have a common skeleton
Compounds with similar structures are likely to have similar bioactivity or pathways of action.
ex) Penicillin, opiates

Classification based on pharmacological effects: Classification based on pharmacological effects or physiological activities;
It is useful to know which kind of medicine works for which disease.
However, there are too many different drugs included in the classification and target different targets.
ex) Analgesic, antipsychotic, antihypertensive

Classification according to target system: Classification according to which target the drug affects in the human body.

Classification according to target molecules: Classification according to molecular targets to which drugs bind
The exact use of the target is unknown only by the name of the target.
ex) Anticolinestrase

1-5 Name of Drug
Component name, code, and trademark name
Exclusive name: Name used by each manufacturer with different compositions;
Used in generics

Properties of drugs

2-1 Chemical properties of materials

Ion
chargeable and water soluble
REGULATING BIOLOGY VIA CONCENTRATION
involved in human homeostasis
Molecule
Electrically neutral and fat-soluble
Regulation by triggering binding or signaling
Engaged in maintaining human function (neurotransmitters, hormones)
It is important to have a three-dimensional structure and conformer - important feature in CADD
Phase 1 metabolism in PK
Phase 2 metabolism in PK
Prodrug: A substance that does not have a medicinal effect becomes effective after metabolism in the body.
Electrolyte: It doesn't generate electricity, but it dissolves in water and generates electricity.
Strong electrolyte: ionic compounds, strong acids
Pharmacolytic electrolyte: weak acid

2-2 Physical properties of materials: intermolecular bonds, solubility

polarizability of molecules
Dipole moment due to the difference in electronegativity of the atoms included
Differences in solubility in water occur and affect metabolic reactions → Recommended Dietary Allowances (RDA)
If the solubility in water is low, accumulation in the body is possible, so RDA is low.
Intermolecular interactions: the binding force of drugs and targets
What weak force is used?
The number and type of attraction depend on the structure of the functional groups and drugs present.
Electrostatic bond: Strongest bond among intermolecular bonds
Coulomb's force: inversely proportional to distance + proportional to charge value

2-3 Acids and bases: pKa

pH = - log[H+]
pKa = -log Ka
Ka = [H+][B-] / [HB]
Henderson-Hasselbalch equation

The ratio of the drug to exist as a molecule or ion in vivo can be known.
Affecting the absorption of drugs through diffusion
Predicting where a drug will be absorbed into the blood.
Ionized drugs are not absorbed into the blood.
Buffer solution

3-1  Target of drug

Protein: Enzymes, receptors, transporters, structural proteins

Proteins are characterized by three-dimensional structure, conformer, and energy minimization.
The structure of the protein originates from the amino acid sequence.
Weak force of amino acid residues
Disulfide bonds between cysteines, or electrostatic bonds, hydrogen bonds, van der Waals, hydrophobic interactions
The hydrophilic and hydrophobic characteristics are different for each region in the three-dimensional structure.
External = hydrophilic, internal = hydrophobic
Drugs must be hydrophobic because they must bind to the pocket of the protein.
The number of amino acids participating in hydrogen bonds, van der Waals attraction, and hydrophobic interactions is high.

TARGETED PROTEINS
Enzyme
As an in vivo catalyst, it lowers the activation energy of the reaction.
Promotion of continuous chemical action without being consumed or changed
The active site of the enzyme is hydrophobic.
Carry out binding, catalysis
mutable due to mutation
Enzymes can infer their function from their names.
Due to polymorphism in the gene, there may be individual differences in the metabolic ability of enzymes.
Control of enzymes
Reversible inhibitor or irreversible inhibitor (drug covalently bound to active site)
Competitive inhibitors (binding to enzymes instead of substrates) vs. noncompetitive inhibitors (changing the structure of active sites)

Transpoter
The passage of extracellular substances, such as neurotransmitters, in cell membranes
Commonly used as a target for antipsychotic drugs

Structural protein: tubulin
tubulin polymerization inhibitor
TUBULIN DEPOLYMERIZATION INHIBITORS (PACILTAXEL)

nucleic acid
Transcription through drugs targeting DNA, involved in replication.
Insertion drug vs. non-insertion drug
Anti-cancer drugs mainly target DNA.
Chain terminator: Suppress DNA elongation
Engaged in translation or signaling processes through drugs targeting RNA.
ex) puromycin: Interference with translation

Cell membrane
ex) amphotericin, gramidicin A: Tunnel can be created within the cell membrane
It can act as an ion transpoter in the cell membrane.

receptor
means of communication between cells
Chemical messenger in which neurotransmitters bind to receptors to promote response
Neurotransmitters and hormones
Neurotransmitter = Through nerves
Hormone = Through blood
The route is different, but it performs the same function.
Receptors have various forms and subtypes
Various receptors are also present in dopaminergic, cholinergic, and adrenergic receptors.
The distribution of receptors in the body is different, and their sequences and functions vary depending on their location.
Receptors, like enzymes, also have binding sites for neurotransmitters.

Differences: Enzymes induce substrate responses, receptors transmit only signals after binding
signaling mechanism

Neurotransmitter and receptor binding → induction matching → protein structural change → receptor activation → intracellular chemical change → various effects

Cell membrane binding receptor
ion channel receptor
Passing only certain ions through the cell membrane (cation or anion)
Combination of several proteins
The tunnel is closed in a resting state, and the tunnel is opened when the messenger is combined.
The reaction rate is fast because the movement of ions is large and fast.
G-protein conjugate receptor
Membrane binding protein that activates G-protein
The most important drug target, 30% of all drugs bind to the receptor.
It often becomes the starting point of signaling cascade.
kinase receptor
Although it is a receptor, when activated by messenger binding, it performs the function of the enzyme.
Phosphorylation at the active site inside the cell when activated
Example) Tyrosine kinase receptor
Phosphorylated substances due to kinase are involved in signaling pathways in the body.

intracellular receptor

Nucleic hormone receptor
receptor present in cell
It plays an important role in regulating gene transcription.
Use sex hormones, steroid hormones, thyroid hormones, retinoids, etc. as chemical messengers
The reaction time is very slow from hours to days.

MODULATION OF RECEPTORS
agonist
Designed by imitating the structure of natural neurotransmitters
Knowledge of the functional group of natural neurotransmitters and the binding site of receptors is important.
Stimulate the function of a desired receptor by adjusting the enantiomer, the number of binders, the position, the size, etc.
Even if it does not imitate natural messengers, it is also possible to design a material suitable for the binding site of the receptor.
ex) Use benzodiazepine for activation of GABA receptors
antagonist
Drugs that bind to receptor binding sites but do not activate receptors
The goal is to block activation through normal messengers.
It can be blocked by designing it to have stronger bonding power than natural messengers.
It is not aimed at the direct coupling position, but is also aimed at the umbrella effect by coupling it to the surrounding coupling position.

from. Song's blog