Ligand Efficiency Metrics & FBDD

Question 1

What is ADMET?

Answer 1

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?

Question 2

What equation gives the ligand efficiency?

Answer 2

LE = -(∆G/HA)

Where HA is the No. of heavy atoms in the molecule

Question 3

What equation gives the lipophilic ligand efficiency?

Answer 3

LLE = pIC50 - clogP

Where clogP is the use of computer software to calculate/predict logP of a compound

Question 4

What is logD?

Answer 4

It is the log of a drugs relative distribution in an n-octanol/water mixture in its ionised and unionised form.

Question 5

What is logP?

Answer 5

log of a drugs relative distribution in an n-octanol/water mixture in its unionised form

Question 6

Define IC50

Answer 6

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

Question 7

What is pIC50?

Answer 7

pIC50 is the negative log of the IC50 value when in molar conc.

Question 8

Why use pIC50?

Answer 8

Because the nature of potency values is logarithmic, and so should be reported as such.

Gives increased accuracy in the number generated.

Question 9

Define ligand efficiency. What is its use?

Answer 9

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.

Question 10

What should the ligand efficiency of a drug compound ideally be above?

Answer 10

0.3

Question 11

What is lipophilic ligand efficiency used for?

Answer 11

It is a parameter used to evaluate the quality of research compounds, linking potency and lipophilicity in an attempt to estimate drug-likeness.

Question 12

What is group efficiency?

Answer 12

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

Question 13

What is enthalpic efficiency?

Answer 13

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.

Question 14

What is lipophilicity-corrected ligand efficiency?

Answer 14

Defined as logP / LE

Misleading as acceptable LELP value even with a low LE - if log P is also very small.

Question 15

What is size-independent ligand efficiency?

Answer 15

Identifies compounds with high LE across a wide range of ligand sizes, tracking their progress during the drug-design cycle

Question 16

What is astex ligand lipophilicity efficiency?

Answer 16

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.

Question 17

What is the Property Forecast Index?

Answer 17

PFI aims to predict how likely a compound is to make it to market based particularly on its solubility

Question 18

What 2 main factors is PFI based on?

Answer 18

1. Lipophilicity should be minimised
2. Most drugs contain at most just a few aromatic rings

Question 19

How is PFI calculated?

Answer 19

PFI = (chromatogram log D7.4) + (# of aromatic rings)

Question 20

What’s the significance of the Property Forecast Index?

Answer 20

Molecules with a PFI value >7 were found to be much more likely to be problematic in terms of solubility, promiscuity and overall development

Question 21

What is an ADMET score?

Answer 21

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

Question 22

Why are LE and LLE both key indices in drug development?

Answer 22

Both important screening components of hit quality assessment

Provide useful contribution to hit advancement decision-process.

Question 23

What is Fragment Based Drug Design?

Answer 23

FBDD methodology is used to find quality leads for optimisation into drug candidates.

FBDD can also accelerate the drug development process

Question 24

What does FBDD consider?

Answer 24

It considers ligand efficiency and the pharmacokinetics of drug-like molecules - involving the use of multiple strategies and concepts under a structured workflow.

Question 25

What’re the advantage of FBDD?

Answer 25

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.

Question 26

What’re the disadvantages of FBDD?

Answer 26

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

Question 27

What’re the 5 steps of FBDD?

Answer 27

Fragment library design

Core fragment generation

Fragment growth

Activity evaluation for new hits

New candidate selection

Question 28

What is the Rule of 3?

Answer 28

Have a molecular weight < 300 Da

Have < 3 hydrogen bond acceptors/donors

clogP ≤ 3

Question 29

What should also be considered in drug design along with the Ro3?

Answer 29

Diversity, complexity, water solubility and lipophilicity of the molecule - increase drug-likeness

Question 30

How do smaller fragments benefit?

Answer 30

A smaller initial fragment means the optimised compound is likely to be smaller - Ro3

Question 31

Describe fragment growing - Concept 6 (Fragment Growing)

Answer 31

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

Question 32

What is scaffold hopping - Concept 7?

Answer 32

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

Question 33

What do scaffolds usually consist of?

Answer 33

Ring systems and linker moieties between rings

These are extracted by removing all other substituents from the original compound

Question 34

What is typically done to a lead compound to achieve scaffold hopping?

Answer 34

Heterocyclic ring replacement, ring opening/closure reactions are 3 common methods to achieve scaffold hopping

Question 35

Why is scaffold hopping so widely applied?

Answer 35

It is often used not only to improve ADMET properties, but to also overcome patent limitations for current leads of competitors

Question 36

What’s bioisosterism?

Answer 36

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

Question 37

Whats the benefit of using bioisosterism replacement?

Answer 37

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

Question 38

Where does ‘fragment and fragment library’ come into the five steps of FBDD?

Answer 38

In fragment library design

Question 39

Where does fragment screening come into the five steps of FBDD?

Answer 39

Core fragmentation design

Question 40

Where does bioisosterism come into the five steps of FBDD?

Answer 40

Activity evaluation for new hits

Question 41

Where does ligand efficiency come into the five steps of FBDD?

Answer 41

Measured throughout the process - in all steps

Question 42

Where does fragment growing come into the five steps of FBDD?

Answer 42

In fragment growing

Question 43

Where does ‘Scaffold hopping’ come into the five steps of FBDD?

Answer 43

Activity evaluation for new hits

Question 44

Where does virtual fragment screening come into the five steps of FBDD?

Answer 44

In core fragment generation

Question 45

Where does ‘binding subpocket’ come into the five steps of FBDD?

Answer 45

Measured continuously - in all steps of process

Question 46

Where does ‘pharmacophore/core fragment’ come into the five steps of FBDD?

Answer 46

In core fragment generation

Question 47

In the discovery of a CDK inhibitor, why was fluorine substituted with chlorine on the aromatic ring?

Answer 47

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

Question 48

Why are piperidine rings, and analogues, added to lead drug candidates?

Answer 48

To improve cell-based activity and in vivo efficacy whilst increasing activity and maintaining ligand efficiency

Question 49

What is Navitoclax used for?

Answer 49

It is used as a combination treatment against solid tumours

Question 50

What’s significant about Navitoclax?

Answer 50

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)