Lecture 5.1 Flashcards
What does the process of ‘hits-to-leads’ rely on?
- availability of compounds
–> quality (e.g. purity)
–> diversity (e.g. structural diversity) - Effective assay system
What are the sources of chemical diversity in identifying hits?
- natural products
–> plants
–> marine organisms
–> fermentation, microbial, animal - Biotechnology (proteins/ nucleic acids)
- Synthesised compounds
How are synthesised compounds ‘synthesised’?
- rational approach
–> based on x-ray diffraction of the biological target - chemical modification of existing
compounds/pharmacophores
What are the sources of compounds for compound libraries?
- isolated natural products from microbes, plants or animals
- collections of discreetly synthesized compounds –> focused around pharmacophores
- random libraries –> combinatorial libraries
What are pharmacophores?
structural features needed to activate or inhibit specific receptors or enzyme active sites
How are combinatorial libraries made?
- Focus on molecules or pharmacophores with known biological activity
- Random selection of diverse representatives
What kinds of chemical libraries are desired in drug discovery?
- high degree of chemical diversity
- compounds are present in sufficient quantity and quality
What is the role of chemists in drug discovery?
After validating hits, optimize efficacy and pharmaceutical properties; structure based inhibitor design
Apart from designing and synthesising a potential drug, what else does drug discovery process entail?
development of testing methods that are needed in the studies of how the molecule operates in the body.
What is medicinal chemistry?
blends synthetic chemistry
natural product chemistry,
molecular modelling,
computational biology,
structural genomics, and
pharmacology to design and discover drug molecules for targets/diseases of
interest.
What was the 1st rational development of a synthetic drug?
Arsphemamine (Salvarsan) with antiprotozoal effect
–> curing syphilis
–> developed by combining synthesis with biological screening and evaluation procedure
What is a ‘lead compound’?
The compound on which a development is based
What is meant by analogues?
Synthetic compounds developed from a lead are referred to as its analogues
What does a Structure-activity relationship (SAR) study consist of?
synthesizing and testing a series of structurally related compounds to reveal the relative usefulness of different compounds
What is Quantitative structure-activity relationships (QSAR) study?
quantitatively correlate the chemical structure of compounds to biological actions using mathematical models.
What is the significance of Quantitative structure-activity relationships (QSAR) study?
The mathematical expression can then be used to predict the biological response of other chemical structures
Many drugs have structures resembling
the ____________ of the drug targets.
endogenous ligands
What approach of drug discovery cannot be applied to orphan receptors?
Modifying the structure of the
endogenous ligand
–> cannot be applied for orphan receptors
What is the random (irrational) approach of drug discovery?
Scan thousands of potential compounds from natural sources for a hit against specific assays
Describe the rational approaches in drug discovery.
determining the structure of the target (e.g. x-ray crystallography)
–> designing a drug to fit the target
What are some modern technologies used for drug design?
- Computer-based Drug Design (CBDD)
- Structure-Based Drug Design (SBDD)
What is meant by descriptors in drug discovery?
quantitative representations of molecular properties that are used to characterize the chemical structure of molecules
–> 1D, 2D and 3D
What are 1D descriptors?
simple property counts
–> polar surface area
–> MW
–> polarisability
–> H-bond doner
–> rings
What are 2D descriptors?
represented by substructure or fingerprints accounting for the presence or absence of particular features
What are 3D descriptors?
take into account the conformational freedom of the compound encoded as a
pharmacophore, 3D fingerprint,
shape or field.
Describe how in silico identification could be used in drug discovery.
- screen database of commercially available compounds for 2D fingerprint similarity to template of receptor agonist
- identify hits, confirm experimentally in an in vitro assay
What recent advances has led to the possibility of virtual (in silico) screening?
- computing power
- high resolution structural determination by x-ray crystallography and NMR
- Availability of sophisticated algorithms
–> interactions of ligands and receptors
Virtual (in Silico) screening of compounds can be conducted through:
- Physical molecular properties
- Chemical property
–> number of H-bond acceptors or donors - Solvation parameters or chemical functionality of a binding pocket of the target protein
What are the advantages of using in silico screening for rational drug design?
- Filter out the majority of compounds that have little chance of hitting a target
- Reduce the number of compounds being screened in bench-top assays
What do static virtual libraries contain?
all virtual molecules that may exist within a certain set of boundaries.
What is ‘structure guided lead optimization’?
only those molecules that are predicted to bind to the target protein are synthesized and tested in the assays.
–> in silico modelling of protein-ligand interactions
What are dynamic virtual libraries?
contain virtual compounds that are relevant to the user’s research question.
–> emphasis on assuring synthetic feasibility
What is the emphasis of dynamic virtual libraries?
on assuring synthetic feasibility
What does Lipinski’s rule of five state?
It states that poor absorption or permeability are more likely when certain conditions are met
Lipinski’s Rule of Five states that poor absorption or permeability are more likely when:
- cLogP > 5
- Molecular mass > 500 daltons (Da)
- No of H-bond donors (OH +NH) > 5
- No of H-bond acceptors (O+N) > 5
Which of the rule of 5 is changing less appreciably?
cLogP
drug lipophilicity is changing less over time than other physical properties
What is cLogP and what is it a measure of?
Calculated Log of the octanol-water partition coefficient
–> a measure of a drug’s lipophilicity.
What happens when the lipophilicity of a proposed drug is too high?
-increased likelihood of binding to multiple targets –> toxic
-poor solubility and metabolic clearance
How is cLogP defined?
ratio of un-ionized drug distributed between the octanol and water phases at
equilibrium
Higher values of cLogP imply greater _______________ .
lipophilicity
Increasing lipophilicity will also tend to increase binding affinity.
True or false.
True.
Because the target site is often hydrophobic in nature.
What are prodrugs?
Prodrugs are compounds that are biologically inactive but can be metabolized to an active metabolite
What are some reasons of designing prodrugs?
- to enhance absorption
- improve patient acceptance
- reduce toxicity
- slow release of drugs in body
- achieve site specificity (only release drug
in the vicinity of its site of action)
What can prodrugs be classified into?
- bioprecursor prodrugs
- carrier prodrugs
What are bioprecursor prodrugs?
contain the embryo of the active species
within their structure
–> active species liberated through metabolism
What are carrier prodrugs?
combining an active drug with a carrier species to form a compound with the desired characteristics
Give an example of a carrier in carrier prodrugs?
a lipophilic moiety to improve transport through membranes
What are the 2 carrier prodrug systems?
- bipartate prodrug system
- tripartate prodrug system
What is bipartate prodrug system?
active species linked to the carrier by forming a functional group (e.g., amide, ester)
What is tripartate prodrug system?
active species linked to the carrier by a link consisting of a separate structure.
The lipophilicity of a drug can be improved by combining a lipophilic carrier with the polar group(s) on the drug so as to improve absorption and transport through membranes.
True or false
True
How can the water solubility of a drug be improved?
by introducing a carrier with a water solubilizing group(s).
What carriers are used to from prodrugs so as to improve taste of drugs?
palmitic acid and other long chain fatty acids
How can the duration of action of drug be prolonged? What carrier to use?
Slow hydrolysis of amide and ester linked fatty acid carriers
Name a drug for which the toxic side effects were reduced by designing an appropriate prodrug
Salicylic acid cause gastric irritation and bleeding
solution –> acetylated salicylic acid (aspirin) –> improve absorption and less irritation
What kind of prodrug carrier are designed to cross blood-brain barrier (BBB) to achieve site specificity?
dihydropyridine ring system-based
carriers
Why are dihydropyridine ring system-based carriers appropriate for crossing BBB?
- ring system has the required lipophilic
character for crossing BBB - ring system can be synthetically modified to allow the link between the carrier and the drug
- Once the prodrug crosses the BBB, the
dihydropyridine can be easily oxidized by
oxidases in the brain - The resulting hydrophilic quaternary
ammonium salt cannot return across the barrier and is relatively nontoxic
