Unit 1 Flashcards
What does the ionisation state of a drug depend on and what will this influence?
The ionisation state of a dug depends on the pH of the medium in which it is dissolved in which in turn influences the solubility of the drug, the way in which it is formulated as a medicine, its absorption and distribution within the body and its pharmacological activity.
Describe how double bonds and triple bonds are formed and their bond angle.
Double bonds also known as alkenes are formed from 1s orbital and 2p orbitals creating 3 sp² orbitals with a bond angle of 120. However triple bonds are formed from 1s orbital and 1p orbital creating 2 sp orbital with an angle of 180.
Describe how sigma and pi bonds are formed.
Sigma bonds are formed by the overlap of sp^n hybrid orbitals. The single bond frameworks the molecule where the electron density is concentrated between the nuclei. However, pi bonds are formed by the overlap of p orbitals. This contains double and triple bonds and restrict rotation.
What effect does stereochemistry have on a drug?
Stereochemistry can effect the the clinical efficiency as the drug depends on the three dimensional structure. It can also have an effect on its toxicity and side effects.
What defines a chiral compound?
If all four attached groups of the sp^3 atom are different, then the molecule cannot be superimposed onto its mirror image (the two isomers are different compounds). These separate chiral isomers are a pair of enantiomers.
What are the possible effects of the mirror image compound?
The mirror image can be either inactive or have other effects such as producing side effects, countering the effect of the drug or being metabolised into a toxic product.
What is diastereoisomers?
These are stereoisomers of each other but are not specifically mirror images of each other.
What are the two types of diastereoisomers?
1) Cis-trans diastereoisomers: found in molecules with double bonds and saturated rings.
2) Chiral diastereoisomers: chiral isomers which are not enantiomers and therefore different in physical, chemical and biological properties. They are only found in molecules with multiple chiral centres.
What is a racemic mixture (racemate)?
An equal mixture of both enantiomers of a compound, has no measurable optical rotation.
What is bond polarity?
This is the sharing of electrons between atoms often unevenly causing partial negative and positive charges.
How does hydrogen bonding occur?
This is when a strongly electronegative atom (oxygen, nitrogen and halogens) approaches a hydrogen atom which is covalently attached to a second strongly electronegative atom. For example, hydrogen bonding can occur between a carbonyl and an amino acid.
Which atom in a hydrogen bond is classed as an acceptor and which one is classed as a donor?
The acceptor in the hydrogen bond is the hydrogen atom attached to the electronegative atom and the donor is the electronegative atom (O, N or F) with one or more lone airs of electrons.
What are some properties of hydrogen bonding?
The hydrogen bond has an optimum length and is linear. This results in the bond being relatively constrained and therefore constrains the distances and orientation between molecules. This allows the hydrogen bond to determine the structure of the proteins and holding together the double stranded DNA molecule. The hydrogen bond is also relatively strong.
How do you identify charge-charge (ionic) interaction?
Any group or atom in a molecule which carries a charge, as a result of either the electronegativity difference between atoms, the presence of an acidic or basic group or an atom with a lone pair of electrons. The interaction can either be attractive with an oppositely charged group or repulsive with a similarly charged group.
What is the difference between hydrophobic and hydrophilic groups?
Hydrophobic molecules are insoluble in water whereas hydrophilic molecules are soluble in water. These molecules can be identified by the presence of polar groups such as carboxylic acid, amine and hydroxyl, making the molecule hydrophilic and the absence of these makes the molecule hydrophobic.
What are the five major groups of amino acids?
- Non-polar (straight or branched chains, may or may not be cyclic).
- Aromatic
- Uncharged polar
- Charged
- Sulphur-containing
Why are amino acids amphoteric?
They contain at least 2 ionisable side chains which can make them react as either acids or basis depending on the pH of the medium. In acidic media (below pKa) the carboxylic group is unionised while the amino group is ionised. In basic media the opposite is true.
What structural elements constitute an amino acid?
Nitrogen and hydrogen
What differentiates polar and non-polar amino acids?
Non-polar amino acids contain mostly hydrocarbons whereas polar amino acids contain a charge.
How are amino acids joined together and what is the resulting molecule known as and consists of what?
Amino acids are joined together by losing a water molecule and the resulting molecule is known as a dipeptide and consists of two amino acids linked through CO-NH amide linkage also known as a peptide bond.
How are specialised protein structure established?
Specialised protein structure is formed after the formation of a new protein (translation) where a few amino acid residues are modified. An example includes 4-hydroxyproline and 5-hydroxyproline which are modified versions of the amino acids proline and lysine, an essential components of collagen.
What is the function of amino acids and their derivatives?
They are chemical messengers between body cells or as intermediates in various metabolic processes. This includes the roles of y-aminobutyric acid (GABA a derisive of the amino acid glutamate) and dopamine (derivative of tyrosine).
What are the 6 categories of proteins and what is there functions?
- Structural proteins: structural support and framework
- Movement proteins: components in muscles
- Transporter: in cell membranes allow the movement of molecules in and out of the cells.
- Metabolic: Catalyses the breakdown & synthesis of biological macromolecules to maintain cellular function.
- Communication: binding of hormones & neurotransmitters to specific cellular receptors.
- Defence & Protection: contribute to the barrier properties of skin such as keratin in immune system.
Describe the four structure of proteins?
- Primary: Simple linear sequence of amino acids
- Secondary: Contains regions of amino acid chains that are stabilised by hydrogen bonds from the polypeptide backbone, creating alpha helix & beta pleated sheets.
- Tertiary: Complex coiling & folding of secondary structure which forms final three-dimensional structure and results in the interaction between the polypeptide chain & surrounding water molecules.
- Quaternary: Interaction between individual polypeptides to form a multi-subunit protein complex.
What are the two main categories of proteins?
- Globular proteins: Irregular rounded shape where the core is made up of non-polar amino acids residues, whilst charged and polar residues coat the outer surface. These are readily soluble in the cytoplasm & other aqueous environment. Make extensive use of alpha helices.
- Fibrous proteins: Linear helical or sheet-like structures due to secondary structure domains of individual strand/beta sheet structures or due to quaternary association of several individual sheets. These are tough & usually water insoluble,playing a protective/ structural role in the body.
How does sickle cell anaemia arise?
This arises due to the substitution of a single cell amino acid in haemoglobin resulting in a mutated haemoglobin with a different primary sequence. The low oxygen tension in sickle cell anaemia alters the shape of HgbS & promotes red blood cell suckling which damages the cell membrane & decreases elasticity. These rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion. The disease is cause by faster than normal destruction of red blood cells.
How can tertiary or quaternary structure be altered?
These structures can be altered by changing conditions such as temperature, pH and ionic composition of the environment. These changes can either be reversible or irreversible depending on the severity of the change in conditions. Permanent loss of structure is also known as denature.
What is pKa ?
This is when the pH at which the ionisation is exactly 50% (how weak or strong the acid is). The lower the pKa value, the stronger the acid & the greater its ability to donate protons.
What’s the difference between a pH > pKa and pH < pKa?
pH > pKa: the solution is more basic than the acid’s tendency to donate a proton leading to the acid existing predominantly in its deprotonated form
pKa < pH: the solution is more acidic, & the acid will exist predominantly in its deprotonated form because the solution is more basic than the acids pKa.
What is Isoelectric Point (pI)?
The pH at which the molecule carries no electrical charge.
Define below pKa1
At vey acidic pH, the carboxylic acid is protonated (COOH), giving the amino acid an overall positive charge.
Define above pKa2
At very basic pH, the amino group is deprotonated (NH2), resulting in an overall negative charge.
How is a dipeptide bond formed?
The joining of amino acids by losing a water molecule through a condensation reaction.
How is Down syndrome diagnosed?
By the presence of an additional third copy of chromosome 21.
What is molecular diagnostics or genetic testing?
A medical test that identify molecular changes in chromosomes, genes, or proteins. The results can confirm/rule out a suspected genetic condition, help determine a persons chance of developing or passing on a genetic disorder or hep predict how quickly they will metabolise specific drugs.
What is biotechnology?
The use of molecular methods to modify and engineer the genetic material of living cells so they will produce new substances/perform new functions.
What is polysaccharides & how are they formed?
Carbohydrates macromolecules, consisting of many monosaccharides connected together via covalent bonds, in both linear & branched chains.
What is oligosaccharides?
Carbohydrates of intermediate chain length between 3 and 10 monomers. They can combine with proteins to form glycoproteins or combine with lipids to form glycolipids.
What is LDL & HDL and what is their role?
LDL: Low density lipoproteins transport cholesterol from liver & intestine to the rest of the body.
HDL: High density lipoproteins remove excess cholesterol & transfer it back to the liver.
What are statins?
A class of drugs used to reduce levels of LDLs.
How does Atorvastatin lower cholesterol?
Blocks the enzyme responsible for producing mevalonic acid, a key precursor to cholesterol.
Decreases cholesterol production and reduces isoprenoid levels, which may impact pro-inflammatory signalling.
What’s the difference between water-soluble & fat-soluble vitamins?
Water soluble vitamins are readily excreted from the body and includes vitamin B & C.
Fat soluble vitamins can be stored long term in the body and includes vitamins A, D, E, K.
What is therapeutic index?
The difference between the efficacious and toxic dose.
What are semi-synthetic drugs?
Drugs derived from natural products & modified to improve potency, reduce toxicity, or increase bioavailability.
Give an example of a semi-synthetic drug?
Simvastatin, which is modified from lovastatin & is 2-3 times more potent.
Why is diacetylmorphine (heroin) more potent than morphine?
It has enhanced analgesic activity but is also more addictive.
What is a common class of semi-synthetic drugs?
Penicillin & cephalosporin antibiotics.
What are synthetic drugs?
Drugs made entirely by chemical synthesis, usually from coal or oil derivatives.
Name 3 examples of synthetic drugs.
Ibuprofen, propranolol, and temazepam.
What is Lipinski’s Rule of 5 & what are they?
A set of criteria predicting whether a molecule is likely to be an orally active drug.
* Not more 5 hydrogen bonds.
* Nor more than 10 hydrogen bond acceptors.
* Relative mass of less than 500.
* An octanool-water partition coefficient logP not greater than 5.
* No more than 10 rotatable bonds.
How do small drug molecules work in the body?
They bind to biological macromolecules (receptors) to produce effects.
What is the “lock and key” analogy for drug action?
The drug (key) binds to a receptor (lock) to produce an effect or block normal receptor function.
What is an antagonist?
A drug that binds to a receptor but blocks its normal function.
What is an agonist?
A drug that binds to a receptor and stimulates or increases its activity.
What are barriers to drug absorption in the body?
Skin, membranes, and cell walls.
Where are most drugs metabolised for elimination?
In the liver.
What is a receptor in drug interactions?
A specific chemical component of a cell that a drug binds to in order to produce a pharmacological effect.
How do receptor proteins function?
They act as intracellular antennas for chemical messengers, transmitting signals that lead to biochemical changes in the target cells.
What is required for a drug to effectively bind to a receptor?
A minimum of 3-point attachment is essential for the desired effect.
How do slight molecular structure changes affect drug efficacy?
Can drastically alter specificity and effectiveness.
Do all drugs interact with receptors?
No, some drugs act outside cells by physical means, such as on the skin or gastrointestinal tract, without binding to receptors.
What are the main types of chemical bonds in drug-receptor interactions?
Covalent bonds, charge-charge (ionic) interactions, hydrogen bonding, and hydrophobic interactions.
Why are covalent bonds rare in drug-receptor interactions?
Because drug-receptor interactions are typically reversible, while covalent bonds are strong and irreversible.
Give an example of a drug that forms covalent bonds with DNA.
Cisplatin, an anticancer drug, crosslinks guanine bases in DNA, blocking replication and leading to cell death.
How do ionic (charge-charge) interactions aid drug binding?
Ionised drugs form electrostatic attractions with oppositely charged receptor sites, e.g. salbutamol binding to its receptor.
Why is hydrogen bonding important in drug-receptor interactions?
It allows stable, directional interactions between the drug, water, and receptor sites.
What are hydrophobic interactions in drug binding?
Non-polar drug molecules interact with non-polar amino acids in receptor proteins, reducing contact with water.
How do some drugs interact with DNA instead of protein receptors?
They chemically modify specific nucleotides, inhibiting replication and transcription.
What is an example of a drug that interacts with DNA?
Cisplatin, which binds to guanine bases, preventing DNA replication and leading to cell death.
Why do hydrophobic drug molecules interact with receptor proteins?
Water molecules exclude non-polar substances, driving hydrophobic molecules together.
Which amino acids commonly participate in hydrophobic drug interactions?
Leucine, isoleucine, lysine, valine, tryptophan, and phenylalanine.
What is the first step in drug discovery?
Opportunity assessment- Identifying an unment clinical need and estimating the potential market.
What must be investigated to identify drug targets?
The molecular biology of the disease, particularly malfunctioning biological macromolecules.
What are common drug targets?
Mostly proteins, but sometime nucleic acids.
Why are antibiotic and antiviral drugs often highly selective?
They target metabolic steps that do not exist in mammalian biochemistry.
Why is designing anticancer drugs difficult?
Tumour cells are almost identical to the patients own cells.
What is required once a drug target is identified?
Validation- proving that altering its regulation produces a useful biological effect.
Why is an assay important in drug discovery?
It allows measurement of the experimental agents’ activity on the target.
What is hit optimisation?
Refining hit compounds to improve potency and reduce toxicity?
Why is ADME important in drug discovery?
The drug must reach its target and stay there long enough to be effective.
What may need to be modified during ADME optimisation?
Solubility, distribution, and metabolism.
