Ligand Efficiency Metrics & FBDD Flashcards
What is ADMET?
Absorption - site of admin to systemic circulation.
Distribution - reversible transfer to/from systemic circulation.
Metabolism - any chemical alteration of the drug to enhance water solubility.
Excretion - irreversible transfer of drug from systemic circulation.
Toxicity - Selectivity? Drug interactions? Accumulation?
What equation gives the ligand efficiency?
LE = -(∆G/HA)
Where HA is the No. of heavy atoms in the molecule
What equation gives the lipophilic ligand efficiency?
LLE = pIC50 - clogP
Where clogP is the use of computer software to calculate/predict logP of a compound
What is logD?
It is the log of a drugs relative distribution in an n-octanol/water mixture in its ionised and unionised form.
What is logP?
log of a drugs relative distribution in an n-octanol/water mixture in its unionised form
Define IC50
It is a measure of the potency of a substance in inhibiting a specific biological or biochemical function by 50%
Values are usually expressed as molar concentration
What is pIC50?
pIC50 is the negative log of the IC50 value when in molar conc.
Why use pIC50?
Because the nature of potency values is logarithmic, and so should be reported as such.
Gives increased accuracy in the number generated.
Define ligand efficiency. What is its use?
It is a measure of the binding energy per atom of a ligand to its binding partner, such as a receptor or enzyme.
Used to assist in narrowing focus to lead compounds - reducing number of useless atoms while maintaining high bioactivity.
What should the ligand efficiency of a drug compound ideally be above?
0.3
What is lipophilic ligand efficiency used for?
It is a parameter used to evaluate the quality of research compounds, linking potency and lipophilicity in an attempt to estimate drug-likeness.
What is group efficiency?
An extension of ligand efficiency, but for groups not whole drug.
It estimates the binding efficiency of parts of a molecule added to an existing lead
What is enthalpic efficiency?
Uses ∆H rather than ∆G
A favourable ∆H for binding of the ligand, then more/stronger bonds exist in the bound state than the free state.
What is lipophilicity-corrected ligand efficiency?
Defined as logP / LE
Misleading as acceptable LELP value even with a low LE - if log P is also very small.
What is size-independent ligand efficiency?
Identifies compounds with high LE across a wide range of ligand sizes, tracking their progress during the drug-design cycle
What is astex ligand lipophilicity efficiency?
LLEAT aims to strip out the non-specific binding interactions a lipophilic molecule experiences when going from water to the binding site in a protein.
Involves the use of a modified free energy of binding.
What is the Property Forecast Index?
PFI aims to predict how likely a compound is to make it to market based particularly on its solubility
What 2 main factors is PFI based on?
- Lipophilicity should be minimised
- Most drugs contain at most just a few aromatic rings
How is PFI calculated?
PFI = (chromatogram log D7.4) + (# of aromatic rings)
What’s the significance of the Property Forecast Index?
Molecules with a PFI value >7 were found to be much more likely to be problematic in terms of solubility, promiscuity and overall development
What is an ADMET score?
It is a comprehensive scoring function for evaluating a chemical’s drug-likeness
It was defined based on 18 ADEMT properties predicted vid admetSAR. These weightings for the final value are then adapted for the use and accuracy of the model
Why are LE and LLE both key indices in drug development?
Both important screening components of hit quality assessment
Provide useful contribution to hit advancement decision-process.
What is Fragment Based Drug Design?
FBDD methodology is used to find quality leads for optimisation into drug candidates.
FBDD can also accelerate the drug development process
What does FBDD consider?
It considers ligand efficiency and the pharmacokinetics of drug-like molecules - involving the use of multiple strategies and concepts under a structured workflow.
What’re the advantage of FBDD?
Huge libraries aren’t required - just good quality libraries.
Fragments can be grown with drug-likeness in mind - ensuring fragment library compounds already meet Ro3.
Fragments can detect allosteric binding sites / create new binding pockets larger molecules cannot
Also have sufficient room to grow fragments as they are of small MW.
What’re the disadvantages of FBDD?
Use of small generic fragments - other labs may see same hits and may be working on similar chemical series.
FBDD tends to start with efficient binders - not strong binders, requiring sensitive detection methods. Can become expensive in time and money
What’re the 5 steps of FBDD?
Fragment library design
Core fragment generation
Fragment growth
Activity evaluation for new hits
New candidate selection
What is the Rule of 3?
Have a molecular weight < 300 Da
Have < 3 hydrogen bond acceptors/donors
clogP ≤ 3
What should also be considered in drug design along with the Ro3?
Diversity, complexity, water solubility and lipophilicity of the molecule - increase drug-likeness
How do smaller fragments benefit?
A smaller initial fragment means the optimised compound is likely to be smaller - Ro3
Describe fragment growing - Concept 6 (Fragment Growing)
It accelerates development of lead compounds
Suitable fragments linked to a core fragment
- to improve its binding affinity
Each subtle step can be monitored
- very attractive strategy
What is scaffold hopping - Concept 7?
It is the replacement of current scaffold with an alternative scaffold that has identical binding points - capable of similar interactions at binding positions
It is based on the perspective that key interactions between ligands and residues at binding sites may be replicated
What do scaffolds usually consist of?
Ring systems and linker moieties between rings
These are extracted by removing all other substituents from the original compound
What is typically done to a lead compound to achieve scaffold hopping?
Heterocyclic ring replacement, ring opening/closure reactions are 3 common methods to achieve scaffold hopping
Why is scaffold hopping so widely applied?
It is often used not only to improve ADMET properties, but to also overcome patent limitations for current leads of competitors
What’s bioisosterism?
Bioisosterism replacement is a way to access a diverse chemical space
It’s when functional groups have similar physiochemical properties and share a wide range of biological activities
Whats the benefit of using bioisosterism replacement?
It creates a diverse chemical space, giving medicinal chemists options for optimising a lead compound with several different groups.
Also allows for differentiating a ‘Me Too’ drug further to avoid patent restrictions
Where does ‘fragment and fragment library’ come into the five steps of FBDD?
In fragment library design
Where does fragment screening come into the five steps of FBDD?
Core fragmentation design
Where does bioisosterism come into the five steps of FBDD?
Activity evaluation for new hits
Where does ligand efficiency come into the five steps of FBDD?
Measured throughout the process - in all steps
Where does fragment growing come into the five steps of FBDD?
In fragment growing
Where does ‘Scaffold hopping’ come into the five steps of FBDD?
Activity evaluation for new hits
Where does virtual fragment screening come into the five steps of FBDD?
In core fragment generation
Where does ‘binding subpocket’ come into the five steps of FBDD?
Measured continuously - in all steps of process
Where does ‘pharmacophore/core fragment’ come into the five steps of FBDD?
In core fragment generation
In the discovery of a CDK inhibitor, why was fluorine substituted with chlorine on the aromatic ring?
To induce a twist in the phenyl ring, allowing it to enter the binding site more effectively, instead of sitting planar.
- Cl is much greater is size than F
Why are piperidine rings, and analogues, added to lead drug candidates?
To improve cell-based activity and in vivo efficacy whilst increasing activity and maintaining ligand efficiency
What is Navitoclax used for?
It is used as a combination treatment against solid tumours
What’s significant about Navitoclax?
It was found using FBDD as HTS fails - Navitoclax inhibits a protein-protein interaction - a massive challenge for med-chemists
Also has a very high LogP (»5) and MW (~970 Da)
