Drug Docking and Design

Question 1

What are the types of drugs?

Answer 1

• Small chemical molecules (e.g. aspirin)
• Simple biologics (e.g. insulin)
• Larger biologics (e.g. somatotropin)
• Complex biologics (e.g. monoclonal antibody)

Question 2

What are biopharmaceuticals?

Answer 2

Biopharmaceuticals (biologics) are large, complex molecules produced using living organisms. These living cells, such as bacteria, yeast, or mammalian cells serve as factories where the biopharmaceuticals are synthesized through biological processes.

Question 3

What are traditional pharmaceuticals?

Answer 3

Traditional pharmaceuticals are small molecules that are chemically synthesized in laboratories through a series of chemical interactions.

Question 4

Differences between biopharmaceuticals and traditional pharmaceuticals

Answer 4

• Complexity: Biopharmaceuticals are more complex because they are made of proteins, nucleic acids, or other large molecules.
• Specificity: Biopharmaceuticals are often highly specific, targeting specific proteins or cells in the body.
• Regulation: Biopharmaceuticals are more highly regulated due to their complexity and their involvement in living organisms. They are regulated for their safety, efficacy, and consistency.
• Cost: Biopharmaceuticals are more expensive to produce due to their complexity and the need for specialised facilities.

Question 5

What is a drug target?

Answer 5

A natural molecular structure involved in the pathology of interest. Can be proteins (receptors, ion channels, enzymes), DNA, RNA and ribosomal targets.

Question 6

What is a lead compound?

Answer 6

A chemical compound or natural product that exhibits some level of biological activity against a specific drug target. This activity serves as a starting point in the drug discovery process.
e.g. aspirin, morphine, penicillin

Question 7

What is druggability?

Answer 7

• How well a therapeutic can access a target.
• The efficacy depends on whether the therapeutic can achieve effectiveness in modulating a specific biological target.
• Known successful target classes are GPCRs and kinases

Question 8

Parameters influencing druggability

Answer 8

• Cellular location of target
• Development of resistance
• Transport mechanisms
• Side effects

Question 9

Lipinski’s rule of 5

Answer 9

<= 5 H-bond donors
<= 10 H-bond acceptors
Mass <= 500 daltons
log (P) <= 5

Question 10

What is ChEMBL?

Answer 10

A manually curated chemical database of bioactive molecules with drug-inducing properties.

Question 11

What is molecular docking?

Answer 11

A process that helps in identifying potential drug candidates by predicting the binding affinity of small molecules to a protein or receptor of interest.

Question 12

What can docking be between?

Answer 12

• protein/small ligand
• protein/peptide
• protein/protein
• protein/nucleotide

Question 13

What are the phases of molecular docking?

Answer 13

1. Placing molecules into the binding site of the target (pose identification)
2. Forecasting the strength between the docked conformation and the target (scoring)
   - The main obstacle is due to the shortcomings of the existing scoring functions

Question 14

What is the docking score?

Answer 14

The value obtained from computational docking algorithms that predicts how well a ligand molecule fits into the binding site of a target protein. A lower docking score typically indicates a better fit or a stronger interaction between the ligand and the protein.

Question 15

What is binding free energy?

Answer 15

A thermodynamics measure that quantifies the strength of the interaction between a ligand and a protein. It represents the difference in free energy between the bound complex and the unbound states. Lower BFE indicates a more stable complex and stronger binding affinity between the ligand and the protein.

Question 16

What is binding affinity?

Answer 16

The strength of the interaction between the ligand and the protein. It is a measure of how tightly a ligand binds to its target protein and is often represented by the association constant (Ka), calculated as the ratio of the concentration of the complex to the product of the concentrations of the individual molecules.

Question 17

Types of scoring functions in molecular docking

Answer 17

• Force field approach
• Empirical approach
• Knowledge-based approach
• Machine-learning approach

Question 18

Force field approach

Answer 18

• Affinities are estimated by summing the strength of the intermolecular Van der Waals and electrostatic interactions between all atoms of the two molecules in the complex, using a force field.
• Intramolecular energies of the binding partners are often included.
• Desolvation energies in the presence of water are considered using implicit solvation methods like GBSA or PBSA.

Question 19

Empirical approach

Answer 19

• Based on counting various types of interactions between binding partners.
• Counting may involve:
  1. Ligand and receptor atoms in contact or calculating the change in solvent accessible surface area.
  2. Scoring function coefficients are determined using multiple linear regression methods.
  3. Interaction terms include hydrophobic-hydrophobic contacts (favourable), and hydrophobic-hydrophilic contacts (unfavourable), reflecting unmet hydrogen bonds which are an important enthalpic contribution to binding.
• One lost hydrogen bond can account for 1-2 orders of magnitude in binding affinity.

Question 20

Knowledge-based approach

Answer 20

• Relies on statistical observations from large 3D databases.
• Derives statistical potentials of mean force based on closed intermolecular interactions, assuming frequent interactions indicate favourable binding affinity.

Question 21

Classical scoring functions

Answer 21

Force-field, empirical, and knowledge-based approaches. They assume linear combinations of their contributions to binding, limiting their ability to leverage large training datasets.

Question 22

Machine-learning approach

Answer 22

Characterised by not assuming a predetermined functional form for the relationship between binding affinity and structural features.
- The functional form is inferred directly from data, making it more flexible.
- Outperforms classical scoring functions in diverse protein-ligand complexes and target-specific complexes.
- Particularly effective in structure-based virtual screening.
- Performance gap widens when target-specific data is available.

Question 23

Difficulties in docking

Answer 23

• When both molecules are flexible there are hundreds of degrees of freedom and an astronomical number of possible conformations.
• Protein/ligand models often treat the protein as rigid.

Question 24

Interactions between drugs and targets

Answer 24

• Van der Waals packing
• Electrostatics
• Hydrogen bonds
• Hydrophobic interactions

Question 25

What is a pharmacophore?

Answer 25

A conceptual representation of molecular characteristics essential for a ligand to be recognised by a biological macromolecule.

Question 26

What is a pharmacophore model?

Answer 26

Pharmacophore models elucidate how various structurally diverse ligands can effectively bind to a common receptor site. These models serve as tools for identifying novel ligands, either through de novo design or virtual screening, that possess the ability to bind to the same receptor.

Question 27

Docking methods - flexible ligand

Answer 27

• Treat the receptor as static and the ligand as flexible
• Dock the ligand into the binding pocket, this generates a large number of possible orientations
• Evaluate and select by the energy function

Question 28

Automated docking

Answer 28

There are many programs available. They all make use of:
- cavities
- surface complementarity
- electrostatics
- full energy function

Question 29

How do we score docked models?

Answer 29

Each orientation is scored using 3 scoring schemes:
1. Shape scoring
2. Electrostatic scoring (calculates electrostatic potential)
3. Force-field scoring (uses force-field potential)
Evaluation depends on either using surface curvature/area, or grid-based evaluation of surface packing

Question 30

What are decoys?

Answer 30

A way of evaluating how well your docking program has done on a target. Decoys refer to a set of molecules that probably won’t bind to your target.

Question 31

Standard consensus

Answer 31

Conditional ‘AND,’ takes only the best molecules from both programs

Question 32

Exponential consensus ranking

Answer 32

Conditional ‘OR,’ takes the best molecules from either program

Question 33

Describe the virtual screening workflow.

Answer 33

1. Library preparation - obtaining of compounds
2. Filtering - structure and ligand-based filtering
3. Experimental validation - in vivo and in vitro assays

Question 34

Describe structure-based virtual screening

Answer 34

1. Structure-based pharmacophore modelling
2. Molecular dynamics simulation
3. Molecular docking

Question 35

Describe ligand-based virtual screening

Answer 35

1. Ligand-based pharmacophore modelling
2. Machine learning algorithms
3. 3D shape similarity search
4. Molecular fingerprints