BPS2022 Drug Discovery and Design HD 86 notes
Drug development - from then to now
Lipinski’s rule of 5
- Function:
- Improve physicochemical properties of drugs
- Used to improve compound solubility
- Used to make compounds smaller
- Improve oral bioavailability (for orally delivered drugs)
- Make compounds smaller and more soluble which was designed to contribute
to increased bioavailability
- The Ro5 is a guideline for drug development. It is not an absolute measure of
whether a drug will be absorbed or not.
- Parameters:
- Hydrogen bond donors ≤ 5 (sum of OHs and NHs)
- Hydrogen bond acceptors ≤ 10 (sum of Os and Ns)
- Molecular mass < 500 Da
- Log P ≤ 5
- Compounds that fail Ro5:
- Antibiotics, antifungals, vitamins, and cardiac glycosides
- These drugs are delivered orally, bioavailable drugs that can cross
membranes
- Two rules must be violated for Lipsinki’s rule to be failed
Developing drugs
- Factors to develop drugs
- Potency, safety, efficacy, stability, toxicity, compatibility with other drugs,
suitability for different demographics, and cost
- Selective toxicity = drugs able to act on (injure, modify) specific cells
while leaving others unaffected
- Compounds can increase in size and complexity to improve potency
- Hydrophobicity can increase and solubility is reduced
- Reduce toxicity over the development process
- Requirements for an effective drug
- Able to treat the indication e.g. disease
- Not too toxic
- Able to be delivered
- Modern Small-Molecule Drugs
- Consist of C, H, N, O, and halogens
- Include metals = for imaging
- Pure and dont contain toxophores or reactive chemical groups
- MW not too high but may exceed 500 Daltons
- Target Product Profile
1
, BPS2022 Drug Discovery and Design HD 86 notes
- Desired target properties for a drug development program
- properties/parameters that need to be optimized or considered
- Properties that change during drug development
- Increase in size and complexity to improve potency
- Hydrophobicity will increase and solubility reduce
- Reduce toxicity over the development process
- What makes an effective drug
- Able to treat the indication
- Not too toxic (all drugs have some toxic effects, even if rare/low)
- Able to be delivered (e.g. oral drugs must be bioavailable)
- Important factors for the patient
- Not too difficult to take (e.g. not large numbers of tablets, inconvenient
dosing requirements)
- Oral is well understood and convenient. Injections can be OK if infrequent or
in clinic or live-preserving (e.g. insulin)
Changes to drug discovery and development over time
- Then: Less ethical and safe → human testing was the norm
- Now: More ethical regulation and safety criteria → in vitro and in vivo testig before
first in human dose
- FDA and TGA regulate drugs and medicines to ensure public health and
safety
- Now: technological advances → screening techniques aiding in TDD and PDD
- Then: Relied heavily on serendipity and chance
- Now: Increased prevalence of biologics in the markets (more complex molecules)
- Now: Release and development of blockbuster drugs
- Now: Increased purity of drugs
- Now: Strict preclinical and clinical studies undertaken to ensure safety and efficacy
- To avoid disasters such as thalidomide (e.g. testing for teratogenic effects -
causing birth defects)
Drug development - target selection
- Drug development
- Categories:
- Discovery
- Target selection
- Target validation
- Lead discovery
- Lead optimisation
- Development
- Commercialisation
2
, BPS2022 Drug Discovery and Design HD 86 notes
Target Identification
- Methods
- Pathophysiology
- Phenotypic drug effects
- Genetic studies
- Drug target acts at a molecular level (interact with proteins)
- Drug action at cellular level, tissues level, and system level
- Therapeutic use in humans
- Drug targets
- GPCR, ion channels, growth hormone receptors, enzymes, DNA, and
nuclear receptors
- Criteria:
- Selected based on function not structure (can target be
inhibited or activated)
- Ability to establish an assay (ability to measure functional
response)
- Selected with an educated guess - likelihood of finding a drug
like inhibitor/activator - chemical tractibility
- Strong rationale for disease link or suitable models to test the
theory behind the drug action
- Ability to separate required effects from undesirable effects
- Ability to demonstrate drug efficacy in clinical settings
- Market (a potential commercial market)
- Be testable
- Then demonstrate that the drug can:
- Produce the required/desired effects at the drug target
- Possess minimal adverse effects at the drug target
- Possess efficacy in a clinical setting
- Pathophysiology
- Incorporates disease pathways and underlying mechanisms involved
- Steps:
- Understand the primary disturbance to normal physiological function
and how it arised
- Identify the molecular/biochemical pathways likely to respond to
therapeutic intervention
- Select key molecules from pathway as possible drug targets
- Disadvantage - identification technique is very SLOW
- Phenotypic drug effects
- Therapeutic agents already identified and on the market are further studied
and analysed for other uses
- Genetic studies
- Gene therapy - using animal models to test for possible molecular targets
3
, BPS2022 Drug Discovery and Design HD 86 notes
- Knockout (KO) animal models
- ‘Genetically engineered’ animal that has had a specific gene
altered/removed to recreate a particular pathophysiology
- Benefits:
- Allows for a better understanding of the role of genes in
diseases
- Allows researcher to ‘tinker’ with possible drug targets to try
and reverse/fix the problem
- Steps:
- Embryonic stem (ES) cells are cultured from mouse
blastocysts
- Construction of targeting vector which contains pieces of DNA
homologous to target gene
- The targeting vector is introduced into ES cells (transfection)
- Homologous recombination allows the targeting vector to find
and combine with the target gene
- Selection of targeted ES cells for the presence of neo and
absence of HSV-tk (cells that contain the wanted gene)
- Injection of ES cells into blastocytes
- Implantation of blastocysts into surrogate mother where they
develop into chimeric embryos
- Birth and breeding of chimeric mice to produce gene-targeted
and normal offspring
- Birth of gene-targeted mice = knockout mice
- Questions:
- Correlation between human and mouse
- Relevance of KO phenotype to developing a small molecule
drug
- Compensation of other genes for the KO
- Relevance of KO throughout the development of adult
behavior
- embryonic lethality prevents target identification
Target Validation
- What:
- Experimental approaches by which a potential drug target can be tested and
given further credibility
- Pharmacological approach
- Genetic approach
- Criteria (questions about the drug target):
- Where is it expressed?
- Look for a ‘message’ (mRNA → microarray or RNA sequencing)
- E.g. expression of a receptor
4
Drug development - from then to now
Lipinski’s rule of 5
- Function:
- Improve physicochemical properties of drugs
- Used to improve compound solubility
- Used to make compounds smaller
- Improve oral bioavailability (for orally delivered drugs)
- Make compounds smaller and more soluble which was designed to contribute
to increased bioavailability
- The Ro5 is a guideline for drug development. It is not an absolute measure of
whether a drug will be absorbed or not.
- Parameters:
- Hydrogen bond donors ≤ 5 (sum of OHs and NHs)
- Hydrogen bond acceptors ≤ 10 (sum of Os and Ns)
- Molecular mass < 500 Da
- Log P ≤ 5
- Compounds that fail Ro5:
- Antibiotics, antifungals, vitamins, and cardiac glycosides
- These drugs are delivered orally, bioavailable drugs that can cross
membranes
- Two rules must be violated for Lipsinki’s rule to be failed
Developing drugs
- Factors to develop drugs
- Potency, safety, efficacy, stability, toxicity, compatibility with other drugs,
suitability for different demographics, and cost
- Selective toxicity = drugs able to act on (injure, modify) specific cells
while leaving others unaffected
- Compounds can increase in size and complexity to improve potency
- Hydrophobicity can increase and solubility is reduced
- Reduce toxicity over the development process
- Requirements for an effective drug
- Able to treat the indication e.g. disease
- Not too toxic
- Able to be delivered
- Modern Small-Molecule Drugs
- Consist of C, H, N, O, and halogens
- Include metals = for imaging
- Pure and dont contain toxophores or reactive chemical groups
- MW not too high but may exceed 500 Daltons
- Target Product Profile
1
, BPS2022 Drug Discovery and Design HD 86 notes
- Desired target properties for a drug development program
- properties/parameters that need to be optimized or considered
- Properties that change during drug development
- Increase in size and complexity to improve potency
- Hydrophobicity will increase and solubility reduce
- Reduce toxicity over the development process
- What makes an effective drug
- Able to treat the indication
- Not too toxic (all drugs have some toxic effects, even if rare/low)
- Able to be delivered (e.g. oral drugs must be bioavailable)
- Important factors for the patient
- Not too difficult to take (e.g. not large numbers of tablets, inconvenient
dosing requirements)
- Oral is well understood and convenient. Injections can be OK if infrequent or
in clinic or live-preserving (e.g. insulin)
Changes to drug discovery and development over time
- Then: Less ethical and safe → human testing was the norm
- Now: More ethical regulation and safety criteria → in vitro and in vivo testig before
first in human dose
- FDA and TGA regulate drugs and medicines to ensure public health and
safety
- Now: technological advances → screening techniques aiding in TDD and PDD
- Then: Relied heavily on serendipity and chance
- Now: Increased prevalence of biologics in the markets (more complex molecules)
- Now: Release and development of blockbuster drugs
- Now: Increased purity of drugs
- Now: Strict preclinical and clinical studies undertaken to ensure safety and efficacy
- To avoid disasters such as thalidomide (e.g. testing for teratogenic effects -
causing birth defects)
Drug development - target selection
- Drug development
- Categories:
- Discovery
- Target selection
- Target validation
- Lead discovery
- Lead optimisation
- Development
- Commercialisation
2
, BPS2022 Drug Discovery and Design HD 86 notes
Target Identification
- Methods
- Pathophysiology
- Phenotypic drug effects
- Genetic studies
- Drug target acts at a molecular level (interact with proteins)
- Drug action at cellular level, tissues level, and system level
- Therapeutic use in humans
- Drug targets
- GPCR, ion channels, growth hormone receptors, enzymes, DNA, and
nuclear receptors
- Criteria:
- Selected based on function not structure (can target be
inhibited or activated)
- Ability to establish an assay (ability to measure functional
response)
- Selected with an educated guess - likelihood of finding a drug
like inhibitor/activator - chemical tractibility
- Strong rationale for disease link or suitable models to test the
theory behind the drug action
- Ability to separate required effects from undesirable effects
- Ability to demonstrate drug efficacy in clinical settings
- Market (a potential commercial market)
- Be testable
- Then demonstrate that the drug can:
- Produce the required/desired effects at the drug target
- Possess minimal adverse effects at the drug target
- Possess efficacy in a clinical setting
- Pathophysiology
- Incorporates disease pathways and underlying mechanisms involved
- Steps:
- Understand the primary disturbance to normal physiological function
and how it arised
- Identify the molecular/biochemical pathways likely to respond to
therapeutic intervention
- Select key molecules from pathway as possible drug targets
- Disadvantage - identification technique is very SLOW
- Phenotypic drug effects
- Therapeutic agents already identified and on the market are further studied
and analysed for other uses
- Genetic studies
- Gene therapy - using animal models to test for possible molecular targets
3
, BPS2022 Drug Discovery and Design HD 86 notes
- Knockout (KO) animal models
- ‘Genetically engineered’ animal that has had a specific gene
altered/removed to recreate a particular pathophysiology
- Benefits:
- Allows for a better understanding of the role of genes in
diseases
- Allows researcher to ‘tinker’ with possible drug targets to try
and reverse/fix the problem
- Steps:
- Embryonic stem (ES) cells are cultured from mouse
blastocysts
- Construction of targeting vector which contains pieces of DNA
homologous to target gene
- The targeting vector is introduced into ES cells (transfection)
- Homologous recombination allows the targeting vector to find
and combine with the target gene
- Selection of targeted ES cells for the presence of neo and
absence of HSV-tk (cells that contain the wanted gene)
- Injection of ES cells into blastocytes
- Implantation of blastocysts into surrogate mother where they
develop into chimeric embryos
- Birth and breeding of chimeric mice to produce gene-targeted
and normal offspring
- Birth of gene-targeted mice = knockout mice
- Questions:
- Correlation between human and mouse
- Relevance of KO phenotype to developing a small molecule
drug
- Compensation of other genes for the KO
- Relevance of KO throughout the development of adult
behavior
- embryonic lethality prevents target identification
Target Validation
- What:
- Experimental approaches by which a potential drug target can be tested and
given further credibility
- Pharmacological approach
- Genetic approach
- Criteria (questions about the drug target):
- Where is it expressed?
- Look for a ‘message’ (mRNA → microarray or RNA sequencing)
- E.g. expression of a receptor
4
