Lecture 8 - The Use of Ligand-Lipophilicity Efficiency (LLE) and Related Parameters in Drug Design and Discovery Flashcards
(23 cards)
Compared to approved oral drugs, what features of synthesised experimental compound lead to their failure in clinical development? What do the properties affect?
- More lipophilic
- Larger
- Less 3D
Properties affect ADMET
What is ADMET? Define each one.
Absorption - process by which drug moves from site of administration to systemic circulation
Distribution - reversible transfer of drug to/from systemic circulation
Metabolism - any chemical alteration of drug by living system to enhance water solubility, hence excretion
Excretion - irreversible transfer of drug from systemic circulation
Toxicity - is drug selective for target? Drug-drug interactions, accumulation, etc.
What things feed into the hit identification process?
- Computationally: virtual screening, docking search, similarity search, de novo design, scaffold hopping
- Fragment-based screening
- Building blocks
- High Throughput Screening (HTS)
- Phenotypic screening
What are the different ways of assessing how drug-like a compound is?
- Rule of five (Ro5)
- Free energy of binding per atom
- Rule of three (Ro3)
- Property forecast index (PFI)
- ADMET score
What are the different ways of measuring ligand efficiency (LE)?
- Ligand efficiency (LE)
- Lipophilic ligand efficiency (LLE)
- Group efficiency (GE)
- Enthalpic efficiency (EE)
- Lipophilicity-corrected ligand efficiency (LELP)
- Size-independent ligand efficiency (SILE)
- Astex ligand lipophilicity efficiency (LLEAT)
LE and LLE are most important so we will focus on these.
What is LE, why is it used and how is it calculated? What is the optimal range (minimum value it should be)?
- Measurement of Gibbs free binding energy per heavy/non-H atom of ligand to its binding partner i.e. receptor/enzyme
- Reduces no. useless atoms in molecules but maintains high bio. activity
- LE = -(delta G)/HA
or - LE = 1.4(-logIC50)/HA
- Should aim to be > 0.3
What is LLE used for and how is it calculated (give equation)? What is the optimal range?
- Used to evaluate quality of research compounds, linking potency and lipophilicity to estimate drug likeness
- Difference between p(Activity) and lipophilicity (clogP or logD)
- Should be > 5
- LLE = pIC50 - clogP
where log P = log of drug’s relative distribution in n-octanol/water mixture in its un-ionised form (P)
clogP = use of computer software to calculate/predict logP
logD = log of drugs relative distribution in n-octanol/water mixture in ionised and un-ionised form (D)
What is IC50 and how are values typically expressed (units)?
- Measure of potency of substance in inhibiting specific biological/biochemical function by 50%
- Quantitative measure that indicates how much of particular inhibitory substance (i.e. drug) is needed to inhibit (in vitro) given biological process/component by 50%
- Bio component = enzyme, cell, cell receptro or microorganism
- Values typically expressed as molar conc.
What is pIC50 and why is it used? What are the graphs like?
- Negative log of IC50
- Since potency values logarithmic, data reported should also be log based
- Dose-response curves = sigmoidal (S-shaped) in log space
- If potency decreases because of mM –> nM, exponential change instead of linear (points more evenly distributed)
- Increased accuracy in numbers generated
What is Kd?
Conc. of ligand needed to occupy 50% of receptors
What is group efficiency (GE)?
Extension of LE, estimates binding efficiency of parts of molecule/groups added to existing lead
What is enthalpic efficiency (EE)?
- Uses delta H rather than delta G
- If binding of ligand accompanied by favourable delta H, more/stronger bonds exist in bound state than in free state
What is lipophilicity-corrected ligand efficiency (LELP)? How is ti represented in equation? Why can it be misleading?
- = LogP/ligand efficiency
- Potentially misleading since compound could have acceptable LELP value even with low LE if logP is also very low
What does size-independent ligand efficiency (SILE) do?
Value offers realistic way to identify compounds with high LE across wide range of ligand sizes, and track progress during drug-design cycle
What is astex ligand lipophilicity efficiency (LLEAT)?
- Strips out non-specific binding a lipophilic molecule experiences when going from water to binding site in a protein
- Involves use of modified free energy of binding
What is the property forecast index (PFI) based on? Give the equation.
- Developed by GSK
- Based on fact that:
- Lipophilicity should be minimised
- Most drugs contain (at most) just a few aromatic rings
- PFI = (Chrom log D7.4) + (no. of aromatic rings) where 7.4 = pH
- PFI >7 causes problems with solubility, promiscuity/ability to interact with multiple targets in body and overall development
- Good at predicting solubility but no correlation with MW
What is the ADMET score? What is it weighted by?
- Comprehensive scoring function for evaluation of chemical drug-likeness
- Defined on basis of 18 ADMET properties predicted via admetSAR
- Weighting determined by 3 parameters: accuracy rate of model, importance of endpoint in process of PK and usefulness index
- FDA approved drugs, small molecules and old withdrawn drugs used to test performance of ADMET score
Which LE indices do we use when? Which are the key indices?
- Depends if molecules of same size are being considered
- Individual companies developed their own indices
- LE and LLE remain key indices but not perfect
- LE key in fragment based drug design (FBDD)
What does FBDD do/find? What does it need to consider? (Hint: clinic, drug development)
- Finds quality leads for optimisation into drug candidates
- Candidates have successfully reached clinic
- Can accelerate drug development stages/processes
- Consider LE and PK properties of drug-like molecules
- Multidisciplinary - bio, physics, chem and computer science
- Involves joint use of multiple strategies/concepts
What are the differences between HTS and FBDD?
HTS:
- Larger compounds
- Screen library against particular target, then look for 1 molecule that binds to target (Hit identification)
- Obtain readout in biochemical assay
FBDD:
- Smaller fragments
- Screen target against fragment library, can get more than 1 fragment binding into pocket
- Fragments must be then linked to make drug molecule
What are the advantages of FBDD compared to HTS? (Hint: drug-likeness, properties of fragments)
- Good quality fragment libraries (less likely with HTS)
- Fragments grown with drug-likeness in mind (many HTS compounds not drug-like so cannot be optimised)
- Don’t need huge libraries for hits
- Fragments detect allosteric binding sites/create new pockets (larger molecules wouldn’t)
- Fragment –> lead, start with low MW (average = 150 Da), provides sufficient room to grow molecule while staying within successfully launched drug chemical space
What are disadvantages of FBDD?
- Fragments generic so other labs may have similar hits/work on similar chemical series
- Projects start with efficient binder instead of tight binders - limits hit detection methods, sensitive methods required
- Some sensitive methods expensive (time and materials)
What are the 5 steps of FBDD?
- Fragment library design (must fit Ro3)
- Core fragment generation
- Fragment growing (joining things together, making bigger)
- Evaluating new hits for activity
- New candidate selection
