Chemistry of Drugs Week 9 Flashcards
What are the first few letters of the greek alphabet?
alpha, beta, gamma, delta, epsilon, zeta
What is the carbon next to a carboxylic acid called?
alpha carbon
What is the carbon 2 carbons away from a carboxylic acid called?
beta carbon
What is the difference between a L-amino acid and a D-amino acid?
L has the NH2 group on the left, D has NH2 group on the right
What are the 2 most relevant side chain interactions?
salt bridges and hydrogen bonds
When will an amino acid be protonated?
when pH is lower than pKa
When will an amino acid be deprotonated?
when the pH is above the pKa
What is a hydrogen bond donor?
the molecule that provides a hydrogen atom in a hydrogen bond
What is a hydrogen bond acceptor?
a species that accepts a hydrogen atom in a hydrogen bond
Which amino acid side chains are hydrogen bond donors?
arginine, lysine, tyrosine (remember mesomeric effect)
Which amino acid side chains are hydrogen bond acceptors?
aspartic acid, glutamic acid
Which amino acid side chains are hydrogen bond donors OR acceptors?
aspargine, glutamine, histidine, serine, threonine
Which amino acid side chains undergo pi stacking?
phenylalanine, tyrosine, tryptophan, histidine
Which properties stabilise the internal structure of a protein and therefore stabilise drug-protein binding?
hydrogen bonds, salt bridges, pi stacking
What are the 4 amino acids that act as nucleophiles in chemical reactions at or near physiological pH?
cysteine, glutamic acid, aspartic acid, serine
When may amino acid sidechains be modified?
at the post-translational level by enzymes
How may amino acid sidechains be modified?
phosphorylation, methylation, acylation
What is monomethylation, dimethylation and trimethylation?
adding 1,2,3 methyl groups to NH2-R group
What are the 7 amino acids with aliphatic side chains?
alanine, glycine, isoleucine, leucine, methionine, proline, valine (a giant iguana likes many perfect vegetables)
What are the 3 amino acids with aromatic side chains?
phenylalanine, tyrosine, tryptophan
What are the 3 amino acids with acidic side chains?
aspartic acid, glutamic acid, cysteine
What are the 3 amino acids with basic sidechains?
arginine, histidine, lysine
What are the 4 amino acids with neutral but polar sidechains?
serine, threonine, aspargine, glutamine
What 3 factors does specificity rely on in biology?
- molecular shape
- chemical complementarity (interactions)
- spatiotemporal overlap
What can specific interactions involving protein be with?
small molecules (substrates or neurotransmitters) or large molecules (other proteins)
Where does specific protein-protein interaction occur?
on the protein surface
Where does specific protein-substrate interaction occur?
in the active site
What is an example of interactions in an active site?
class A beta-lactamases in antimicrobial resistance
What are b-lactam antibiotics?
most prescribed antibiotic class, includes penicillin
What do b-lactam antibiotics do?
target enzymes called pencillin-binding proteins (PBPs)
What do pencillin-binding protein do?
they are involved in the biosynthesis of the cell wall in gram-negative bacteria and are irreversibly inhibited by b-lactam antibiotics
What are b-lactamases?
a class of enzymes found in some gram-negative bacteria that hydrolyse the amide bond of the 4-membered b-lactam ring in antibiotics
define drug design
the identification of an API and its optimisation
What are the 3 main sources of drug molecules?
- natural sources
- semi-synthetic
- synthetic
define semi-synthetic drugs
drugs that was a natural source and has been modified a little in the lab
define synthetic drug
a drug made entirely in the lab
What are the advantages of semi-synthesis?
- parts of molecule may be too complex to make in the lab
- finite resources
- modification can result in better specificity
What are the advantages of synthetic drugs?
- reliable, NOT from finite source
- cost effective as from small abundant molecules
- quality control
What are the disadvantages of synthetic drugs?
- limited chemical space –> limited reactions we can do
- limited number of steps we can use
- identity of the target is unknown
define rational drug design
the process of rationally discovering the identity of an API using many techniques and methods
What are the 8 main steps in the drug development process?
- identify the disease
- isolate the protein involved in the disease
- preclinical testing
- find effective drug
- formulation
- scale up
- human clinical trials
- FDA approval
What are the 3 main ‘druggable’ targets?
enzymes, receptors, ion channels
What makes a compound a drug molecule instead of an organic molecule?
it has properties that give a biological response
What are 4 main properties of drug-like molecules?
- low molecular weight
- not too lipophilic
- not too hydrophilic
- presence of functional groups
What are the 3 main properties of druggable targets?
- usually a protein
- leads to a biological response
- does not cause toxicity
Which rule quantifies drug-like properties?
Lipinski’s rule of 5 -> a drug should have these properties
define bioisosteres
structurally distinct molecular fragments (functional groups)
What is the main reason some drugs fail to make it to market?
their chemistry means their efficacy is not high enough and simply do not have a biological effect
How are genomics used in modern drug design?
- identify differences in mRNA in disease state
- can identify changes in the proteins
What is high throughput screening?
a technique where large numbers of chemical compounds are rapidly tested for ‘activity’ against a chosen drug target
What is virtual screening?
a process that uses computational methods to predict:
1. how a compound will bind to a target
2. what compounds might bind to a target (protein)
3.how strongly
What is protein crystallography?
a technique that can reveal the 3D structure of a protein and its bound compounds through crystallisation
What is combinatorial chemistry?
a set of techniques for producing large numbers of compounds in a short period of time, using defined reaction routes and a large number of start materials and reagents
What is molecular modelling?
taking a molecule and putting it into a crystal structure of a drug and trying to minimise the energy to look for favourable and unfavourable interactions
What are ADME techniques?
techniques that help model how a drug will likely act in the body (ADME)
What are in vitro techniques?
using compounds on real tissue samples
What are in silico ADME models?
computational methods that can predict compound properties that are important to ADME, such as LogP, solubility, permeability and cytochrome P450 metabolism
define biological
a medicinal products which is produced by, or derived from, a living system or extracted from a biological source
How are proteins different to small molecule drugs?
- much BIGGER
- synthesis by biochemical reactions within cells
- usually very hydrophilic
- not membrane permeable
How do proteins active receptor signalling?
they bind to a ligand to cause a physiological response
How are monoclonal antibodies produced?
- population of B cells (clones) are derived from a single ancestral B cell
- the antibodies are produced by plasma B cells in the blood in response to foreign substances
How do proteins inhibit receptor signalling?
if binding of a ligand causes a harmful physiological effect, proteins may inhibit a receptor
How do monoclonal antibodies prevent harmful physiological responses?
they bind to a receptor to stop another ligand binding to that receptor, so block a harmful reponse
What is an example of a monoclonal antibody preventing a harmful response?
- Human Epidermal growth Factor Receptor (HER) monomers 1,2,3, and 4 are inactive
- HER2 is the preferred binding partner of the other three and is overexpressed in some cancers
- a ligand binding to HER2 forms a HER dimer and activates it causing cell growth
- Herceptin is a monoclonal antibody which binds to HER2 and stops it dimerising with another HER molecule
What are the steps of production of therapeutic monoclonal antibodies? (hybridomas)
- immunisation
- separation
- fusion
- selection
- expansion
immunisation
BALC/c mice are immunised with an antigen to stimulate antibody production
separation
the antibody producing B cells are isolated
fusion
B cells are fused with myelomas (cancer cells) to generate hybridomas and grow rapidly and produce antibodies
selection
hybridomas producing many antibodies are selected
expansion
expansion of the selected hybridomas to produce monoclonal antibodies
Which two ways is therapeutic protein production scaled up?
bacteria and yeast, mammalian cells
Which two methods are proteins irreversibly inactivated?
conformational changes and chemical changes
How do proteins undergo irreversible conformational changes?
formation of the incorrect structure, which inactivates the protein, may also be by aggregation
define aggregation
multiple protein molecules aggregating together into a large mass
How may proteins be chemically changed and inactivated?
hydrolysis, oxidation, deamidation etc and peptide backbone may break and residues are modified
What are operations that may denature or aggregate proteins?
pH, salt, freezing and thawing, contact with silicone oil
How does silicone aggregate proteins?
the silicone is hydrophobic and the hydrophobic parts of the protein may be exposed to it
What else can cause protein aggregation?
interfaces e.g. air-water, oil-water, hydrophobic surfaces
define gene therapy
replacing a faulty gene with a functional one to cure a disease
How does DNA mutation lead to disease?
leads to a faulty protein OR increased levels of a particular protein
define RNA interference
when small pieces of RNA can stop protein translation by binding to the mRNA that codes for those proteins, decreasing expression of that protein
What is small interfering RNA (siRNA)?
a short, double-stranded RNA molecule that can be used to target and degrade specific messenger RNA (mRNA) sequences
How does siRNA act on mRNA?
- double stranded RNA is cleaved into a shorter segment
- helicase unwinds it into ssRNA
- ssRNA binds to complementary single strand of mRNA
- mRNA is cleaved and can no longer produce the proteins
What is micro RNA (miRNA)?
a 22 nucleotide single stranded RNA (ssRNA) -> they are important in regulating gene expression
What does miRNA do?
it does NOT cause mRNA destruction, but represses or destabilises target mRNA
How can miRNAs be used to treat disease?
overexpressed miRNAs can be inhibited by anti-miRNAs, which are complementary nucleotides that bind to the miRNAs causing the issue
How do RNA vaccines work?
- by introducing a piece of mRNA that corresponds to a viral protein, usually a small piece of a protein found on the virus’s outer membrane
- the body raises antibodies against them
What is cell therapy?
a therapy that involves delivering cells to a patient to correct disease or damage
What is CAR T cell therapy?
T cells are taken from the patient and engineering to have a special antigen receptor that can recognise an antigen on cancer cells and attack them
What are the steps of CAR T cell therapy?
- remove blood from the patient to collect their T cells
- make CAR T cells in the lab
- grow millions of these cells
- infuse CAR T cells into patient
- the CART T cells bind to cancer cells and kill them
What is gene editing?
permanently editing the genome to correct a defect or prevent expression of a specific gene, or activate a gene
What are the 3 methods of gene editing?
gene disruption, gene correction, gene insertion
What is tissue engineering?
replacing diseased or damaged living tissue with living tissues made for the needs of an individual
What are the steps of tissue engineering?
- isolate cells
- expand cell number
- seed the cells on a suitable scaffold
- culture the cells under suitable conditions to generate a mature tissue
- implant the tissue into the patient
What is 3D bioprinting?
printing tissues or organs to replace those damaged or diseased in a patient
What is controlled drug delivery?
long-term release of a drug over a very long period of time
How is controlled drug delivery done?
entrap the drug in a polymer matrix, and either:
1. the polymer slowly degrades and releases the drug
2. the polymer does NOT degrade, and the drug slowly diffuses
What are 4 methods of targeted drug delivery?
antibody-drug conjugates, oncolytic viruses, enhanced permeability and retention effect, use of bacteria to fight cancer
How does targeted drug delivery by antibody-drug conjugates work?
the monoclonal antibody binds to an antigen on the target cells and delivers a drug to that cell
How does targeted drug delivery by oncolytic viruses work?
viruses selectively kill tumour cells
How does targeted drug delivery by the enhanced permeability and retention effect?
blood vessels in tumours are leaky, but poorly drained, so macromolecule and nanoparticle drugs can accumulate in tumours, enhancing targeted drug delivery
How does targeted drug delivery by the use of bacteria to fight cancer?
- oxygen-deficient (hypoxic) areas of tumours tend to be resistant to chemotherapy and radiotherapy
- obligate anaerobe bacteria can colonise in hypoxic areas of tumours
