Lecture 1 - Chemical Bonds and Drug Discovery Flashcards
What occurs during Phase I of clinical trials?
First time tested in humans
Uses healthy male volunteers
Identify adverse reactions, safety, pharmacokinetics and pharmacodynamics
What occurs during Phase II of clinical trials?
Uses several hundred volunteers
Determines clinical effectiveness and optimum dose
What occurs during Phase III of clinical trials?
Uses several thousand volunteers
Determines effectiveness of drug compared to gold standard treatment
What occurs during Phase IV of clinical trials?
Continuous monitoring of drug after release
Identification of rare side effects
Drug can be recalled if needed
What is selective toxicity?
The drug must kill only the target cells and cause no harm to the healthy cells
Name the 8 types of chemical bonds/interactions
Covalent bond Electrostatic/Ionic bond Hydrogen bond Van der Waals interactions Dipole-dipole interactions Ion-dipole interactions Ion-induced dipole interactions Hydrophobic interactions
Describe the covalent bond and give an example of when it occurs
Shared pair of electrons
Quite strong, long lasting
Typical of ‘irreversibly’ binding ligands
E.g. the disulfide bond between two thiol (SH) groups of two cysteine residues
Describe the features of non-covalent bonds
Reversible
Drug-receptor interactions are most commonly non-covalent
Occurs at many sites at once
Describe the electrostatic/ionic bond and give an example of when it occurs
Electrostatic attraction between two oppositely charged ions
Strength inversely proportional to distance between the ions
Usually responsible for initial interaction as drug docks to target
E.g. between NH3+ and COO-
Describe the hydrogen bond and give an example of when it occurs
Forms between a donor (e deficient H atom - usually covalently bonded to an electronegative heteroatom) and an acceptor (electron rich heteroatom - usually O or N with lone pair)
One is weak but cumulatively they are strong
E.g. found between DNA bases
How do hydrogen bonds differ from normal ionic bonds?
The orbital on the hydrogen bond acceptor (1p) interacts with the orbitals involved in the covalent bond between the hydrogen bond donor and it’s electronegative heteroatom
What is the name of the bond formed in hydrogen bonding and what is the bond angle?
Sigma bond
180 degrees
Describe Van der Waals forces
Occurs between two hydrophobic regions
A transient dipole occurs in one molecule due to uneven distribution of electrons
Induces dipole in neighbouring molecule
Individually weak but many can form over large protein surface area
Describe dipole-dipole interactions
A PERMANENT dipole arises in a functional group in the drug (such as C=O)
Aligns in parallel with a local dipole moment in the binding site
Describe ion-dipole interactions
A PERMANENT dipole arises in a functional group in the drug (such as C=O)
Aligns in parallel with an oppositely charged ion in the binding site
Stronger than dipole-dipole interactions because a full charge is involved
What is an ion-induced dipole interaction
An ion induces a dipole within a non-polar molecule
Describe hydrophobic interactions
Drug and target are both solvated. If the desolvation energy is greater than the stabilisation energy gained through binding, the drug will be ineffective.
Hydrophobic regions cannot be solvated - water molecules form ordered structure. When two hydrophobic surfaces interact, the surrounding ordered molecules become ‘freed’ and there is a gain in entropy and binding energy
What factors influence which diseases pharmaceutical companies choose to develop treatments for?
Economic - is the government rich enough to pay, is the disease very prevalent
Medical - treat the most severe diseases
What is an orphan disease?
Rare diseases not normally focussed on by pharmaceutical companies as they are unlikely to make much profit from them
The government will put economic incentives in place to facilitate development of orphan drugs i.e. protocol assistance
What factors should be considered when choosing a drug target?
What is the target (RICE, nucleic acid)
Is the drug an agonist, antagonist, inverse agonist
Does the drug need selectivity between species i.e. penicillin targets cell wall synthesis, human cells don’t have walls
Does the drug need selectivity between targets i.e. antipsychotics would have less side effects if they were selective for D2 rather than D2 and D3
What are the desirable features of a bioassay?
High throughput screening (HTS)
Validity - reliable and clear cut
Cheap
Sensitive and selective - no false positives or false negatives
Name two types of bioassay
Radioligand binding assay - tells you how well a ligand binds to a receptor by measuring radioactivity before and after attempt to displace
Functional assay - radioactive GTP (GTP-gamma-S) binds irreversibly to Galpha subunit. Tells you how activated a GPCR is
Name 10 sources of drug discovery and name an example for each
Plant kingdom - Opioids Microbiological world - Penicillin Marine world - Acyclovir Animal kingdom - Epibatidine (analgesic) Venoms & toxins - Captopril (ACE inhibitor) Medical folklore - Dantron (laxative) Natural ligands - AZT, thymidine analogue Existing drugs - Captopril --> Enalapril Computer aided design Serendipity - Viagra
What determines the strength of a hydrogen bond?
How electronegative the atom bonded to the H atom is
How electronegative the bond acceptor is
Give an example of an ion-induced dipole interaction
The cation-pi interaction A cation (e.g. positive quarternary ammonium ion) interacts with an electron rich region (e.g. aromatic ring). The charge on the ion distorts the pi electron cloud to induce a dipole moment. The ring moves to stabilise the positive charge Utilised by acetylcholine
