Drug Discovery and Design 1 Flashcards
What are the two major stages of drug discovery? What does it involve?
- Preclinical stage: involves the use of in vitro/in vivo testing procedures
- Clinical stage: involves testing/evaluation of drug candidate(s) in human subjects for efficacy and safety
What are the 10 stages for the drug pipeline? Divide these stages into the preclinical stage and clinical stage.
Preclinical stage
- Target discovery (identify biological component involved in disease for the proposed drug to target/counteract)
- Target validation (would targeting enzyme X lead to a reduction in the clinical symptoms of disease Y)
- Assay development (analytical, in vitro, in vivo processes/models for compound testing)
- Drug screening (finding a lead compound)
- Lead Optimisation (adjustment/modification of original lead compounds)
- Preclinical drug development
Clinical Stage
- Phase I trials (healthy human subjects to assemble biological, safety and dosing data such as MTD)
- Phase II trials (pilot studies in small scale diseases human subjects for efficacy and safety trials)
- Phase III trials (large scale studies in diseased human subjects to establish an overall risk-benefit relationship)
- Phase IV trials (post-market approval medical studies to monitor patient health/outcomes and long term safety profile)
Example of Drug Discovery for Tuberculosis? What are the stages?
Target ID validation –> HTS (HIT) –> Hit selection –> lead –> lead optimisation –> preclinical selection –> human phase trials
What does SAR mean?
Structure-activity relationship (SAR)
- how chemical structures affect the biological activity
What does SPR mean? What are the advantages of good properties?
Structure-property relationship (SPR)
- how the drug-like physicochemical properties alter upon structural variation
Advantages of good properties: enable good absorption, distribution, low metabolism, reasonable elimination and low toxicity
What does medicinal chemistry mean?
The branch of chemistry that focuses on the design, synthesis, and development of new medicines
> majority of medicines are small organic molecules
> early medicines are often alkaloids (nitrogen-containing plant products) e.g. morphine and ephedrine
How has identification of drug structures changed from early 1900s to now
Early 1900s: Descriptions include method of isolation, physical appearance, melting point rather than chemical structures
Now: Advances in purification methods such as U/HPLC, NMR, MS,cryo-EM, x-ray crystallography allow for structural determination of these active biomolecules
what are drug targets?
Interact with a specific macromolecular target
- Receptors: typically on cell membranes
> GPCRs (G-protein coupled receptors) and ion channels
- Enzymes: intracellular
- Transporters: extracellular, intracellular
- Nucleic acids: nucleus
What happens at a molecular level when a drug attaches to a target? What are the intermolecular forces?
Binding (through intermolecular bonds) –> conformational change –> activity
A drug is just a collection of functional groups in a specific orientation
Intermolecular forces: ionic, covalent, ion-dipole, ion-induced dipole, hydrogen bond, van der Waals
Why is there a bigger/more accessible pocket for drugs to bind to in COX-2 compared to COX-1?
Key amino acid difference. Ile-523 (COX-1) vs Val-523 (COX-2).
> Conformational change allows for a bigger, more accessible binding pocket in COX-2
What is a lead compound? How is it selected?
Bioactive compound(s) resulting from a drug screening process which shows the desired pharmacological properties
> lead compound (s) is selected from a set of ‘Hit’ compounds (Hits) generated from primary screening
What are the two initial properties of lead compounds?
- Initial bioactivity for a lead compound may not be high – usually possess medium range potency, e.g. micromolar IC50 values
- Initial lead molecules may have undesirable physiochemical properties
What are the three sources for lead compounds?
- NATURAL SOURCES –> most traditional source of drugs but lengthy and expensive screenings
- SYNTHETIC CHEMISTRY –> small-molecule organic compounds. Involves screenings of a large set of compounds against a biotarget(s), pathogen or disease state/condition in animal models
- RATIONAL DRUG DESIGN: structure-based drug design (SBDD) if known structures.
Lead compound with a novel structure unlike any known existing drug is called a NEW CHEMICAL ENTITY (NCE)
What is high throughput screening (HTS)?
> used in big pharmaceutical companies due to high costs
> key stage in pre-clinical drug discovery
It is used to find a lead compound that may be used against a bio target to potentially treat adverse disease/condition –> rapid assessment of bioactivity for a large number of compounds against a particular bio target
- Using in-vitro assays –> most fundamental form of screening
- In Vivo screening expensive and labor-intensive –> occur only after in vitro assays
Why does high throughput screening occur in invitro essays and not in vivo (in a living organism)?
In vivo screening assays are expensive and labour intensive, therefore typically occur only after sets of various available in vitro assays
What are the two common approaches to the drug discovery process? What does it depend on?
Phenotypic screen: target unknown (“blackbox”), faster, multiple targets/interactions
Target-based screen: slower, often avoid off-target activities, high reproducibility (target known)
Mostly dependent upon the available information on the structural aspects of the drug target
For combinatorial chemistry;
A) What does it involve?
B) How is related to high throughput screening (HTS)?
C) What happens when it is combined with parallel synthesis
A)
- Involves simultaneous synthesis of large libraries of chemically related compounds from discrete sets of chemical building blocks
B)
- Allows preparation of compound libraries for HTS
- Like HTS, it is automated and employs multi-well plates as mini reaction chemical vessels
C)
- Allow for rapid automated synthesis, purification, analysis and screening of large compound libraries
Waht does the term Lead Optimisation mean? What does it involve?
Identify lead compound –> SAR and identification of a pharmacophore –> synthesis of analogues (drug optimization) –> identification of a drug candidate.
Complex, non-linear repetition of chemical refinement/modification of a lead compound into a viable drug for clinical use –> changes a lead compound into a more drug-like entity by improving its pharmacokinetic properties (ADME-Tox). Does this by addition, removal and/or modification of certain functional groups/atoms.
Involves:
- SAR (structure-activity relationship)
- SPR (structure-property relationship)
> Studies for evualation in subsequent clinical trials
What is the aim of the structure-activity relationship (SAR)? What is the process by which this is accomplished?
SAR: Identify which functional groups are important for binding affinity and/or functional activity. Allows identification of the pharmacophore
Process
- Alter, remove or mask a functional group
- Test the analogue for binding affinity and/or functional activity
What is the aim for Structure-property relationships (SPR)?
Good properties enable good absorption, good distribution, low metabolism, reasonable elimination, low toxicity.
What is the importance of in in-vitro assays and affinity for SAR (structure-activity relationships)? Provide 4 examples.
In-vitro: outside of living organism
- In vitro binding assay: tests for binding interactions with target
- In vitro functional assay: end-point measurements, e.g. calcium flux, antimicrobial/antiviral assay, etc.
- If in vitro affinity drops: implies the group is important for binding
- If in vitro activity is unaffected, it implies group is not important
in vivo: proof of concept studies, formulation, bioavaliability
What is the meaning of pharmacophore? How is it related to the structure-activity relationship SAR?
Pharmacophore: an ensemble of steric and electronic effects required for ligands to bind effectively to the intended biological target and the consequent biological response
> SAR allows identification of the pharmacophore
For lead optimization, name the 9 strategies that enhance binding interactions to target and briefly explain how.
- Vary alkyl substituents –> vary length and bulk of group to optimize interaction and introduce selectivity. Replace alkyl substituents on heteroatoms (any atom that is not carbon or hydrogen).
- Vary aryl substituents –> vary actual substituents, vary substitutional pattern
- Extension –> explore target binding site for futher binding regions to achieve additional binding interactions (ADD EXTRA FUNCTIONAL GROUP)
- Chain extensions/contractions –> useful if the chain is present connecting two binding groups, vary the length of chain to optimize interactions
- Ring expansions/contractions –> to improve overlap of binding groups with their binding regions
- Ring variation –> replace aromatic/heterocyclic rings with other ring systems (done for patent reasons)
- Isosteres –> replace a functional group with a group of the same valency
- Simplification –> retain pharmacophore and remove unnecessary functional groups
- Rigidification –> rigidify molecules to limit conformations
What are isosteres? What is the rationale in using them in drug design (5 reasons)?
Isosteres: Atoms/groups which have the same valency (number of outer shell electrons), i.e. electronically similar
> isosteres for O = NH, CH2 (6e-) and OH = SH, NH2, CH3 (7e-)
Isosterirsm: Replacement of a group/atom within a compound with a group/atom with similar properties
Rationale for isosteres
- Replace a functional group with a group of same valency
- Leads to more controlled changes in steric/electronic properties
- May affect binding and/or stability
- May alter the physiochemical character
- Can determine whether a particular group/atom within a compound is involved in a bio-target binding interaction
