11 & 12 Advanced Techniques in Computational Drug Design

Question 1

What is molecular modelling?

Answer 1

Use of computers in chemistry to model molecular structures and properties

Molecular modelling is essential in modern medicinal chemistry.

Question 2

How has the accessibility of molecular modelling changed?

Answer 2

It used to require large computing resources; now it can be performed on a desktop computer.

Question 3

What are the three common methods of computational chemistry?

Answer 3

• Ab initio
• Semi-empirical
• Empirical (Molecular Mechanics)

Question 4

What does ‘Ab initio’ mean in computational chemistry?

Answer 4

Latin for ‘from the beginning’; a method that uses quantum mechanics with few assumptions.

Question 5

What type of molecules is ‘Ab initio’ applicable to?

Answer 5

Small molecules using a single PC.

Question 6

What is the main characteristic of semi-empirical methods?

Answer 6

Approximate and faster version of Ab initio; uses some experimental parameters.

Question 7

What is the focus of empirical (molecular mechanics) methods?

Answer 7

Treats atoms like balls and bonds like springs; suitable for large molecules or systems.

Question 8

What is molecular dynamics?

Answer 8

Calculating structures and properties of bulk matter where molecules move under a theoretical model.

Question 9

What is the purpose of energy minimisation in molecular modelling?

Answer 9

To achieve a stable structure by correcting unfavourable bond lengths, angles, or interactions.

Question 10

What is the significance of partial charges in molecular properties?

Answer 10

Indicates how valence electrons are distributed around electronegative and electropositive atoms.

Question 11

What does Molecular Electrostatic Potential (MEP) help analyze?

Answer 11

How a set of molecules may align themselves to interact with electron-rich and electron-poor sites.

Question 12

What is the similarity principle in drug design?

Answer 12

Similar molecules usually possess similar properties.

Question 13

What is the role of a pharmacophore in molecular modelling?

Answer 13

To overlay key features of interest in a molecular structure.

Question 14

How is the active conformation of a drug determined?

Answer 14

By identifying the conformation that allows for optimal binding interactions.

Question 15

What are the two types of drug design strategies mentioned?

Answer 15

• Structure-based design
• Ligand-based design

Question 16

What is virtual screening in drug design?

Answer 16

Calculating properties or activities of molecules before synthesizing them.

Question 17

What does the term ‘molecular graphics’ refer to?

Answer 17

3D visualization of results from molecular calculations.

Question 18

What is the importance of molecular orbitals (HOMO and LUMO)?

Answer 18

They explain the reactivity of molecules.

Question 19

What does RMSD stand for and its role in structural comparisons?

Answer 19

Root Mean Square Distance; measures similarity between molecular structures.

Question 20

True or False: The active conformation of a molecule is always the lowest energy conformation.

Answer 20

False.

Question 21

What is the significance of the dielectric constant of water in molecular charge distribution?

Answer 21

It masks electrostatic interactions in a hydrophobic environment.

Question 22

What is the purpose of using rigid analogues in drug design?

Answer 22

To define the geometry of key binding functionalities.

Question 23

Fill in the blank: The three common techniques of computational chemistry are _______.

Answer 23

[Ab initio, Semi-empirical, Empirical (Molecular Mechanics)]

Question 24

What are the typical applications of molecular dynamics?

Answer 24

• Energy minimisation
• Conformational analysis
• Molecular motion

Question 25

What is the role of X-ray crystallography in drug design?

Answer 25

To identify the active conformation of proteins and ligands.

Question 26

What is a pharmacophore?

Answer 26

An ensemble of steric and electronic features necessary for optimal supramolecular interactions with a biological target ## Footnote A pharmacophore triggers or blocks a biological response and is an abstract concept, not a real molecule.

Question 27

What are the pharmacophore descriptors used to define a pharmacophore?

Answer 27

* H-bond donors * H-bond acceptors * Aromatic rings * Acidic groups * Basic groups ## Footnote These descriptors characterize the interaction capabilities of a group of compounds towards their target.

Question 28

How can a pharmacophore be identified from a range of active compounds?

Answer 28

By overlaying molecules and identifying common pharmacophoric features. ## Footnote This is especially useful when the structure of the target is unknown.

Question 29

What is the purpose of virtual screening in drug design?

Answer 29

To ensure that structures can adopt a stable conformation containing the required pharmacophore. ## Footnote It helps in analyzing 3D pharmacophores.

Question 30

What is the first step in planning combinatorial synthesis?

Answer 30

Identify pharmacophores for all conformations of the most rigid structure. ## Footnote This process helps to reduce the number of structures synthesized.

Question 31

What does docking in drug design involve?

Answer 31

Determining the best alignment of two molecules, such as a ligand and a protein. ## Footnote It is crucial for predicting protein/ligand interactions.

Question 32

What are the levels of complexity in docking?

Answer 32

* Protein and ligand both rigid (simplest) * Protein rigid and ligand flexible * Protein and ligand both flexible (most complex) ## Footnote Most studies use the second approach.

Question 33

What is the purpose of manual docking?

Answer 33

To arrange binding groups on the ligand with complementary groups of the binding site. ## Footnote It involves rigid docking where both molecules remain in the same conformation.

Question 34

What is a pose in the context of docking?

Answer 34

A specific set of rotational, translational, and torsional parameters for a ligand in a binding site. ## Footnote Each ligand conformation can have a huge number of poses to explore.

Question 35

What is a genetic algorithm in docking?

Answer 35

A method that uses concepts from biology to explore a large search space of molecular conformations. ## Footnote It involves 'survival of the fittest' to select the best binding conformations.

Question 36

What factors are considered in estimating binding energy?

Answer 36

* Desolvation enthalpy and entropy * Protonation state * Distortion energy * Dipole moment * Loss of translational and rotational degrees of freedom * Binding enthalpy ## Footnote These factors are crucial for understanding protein-ligand interactions.

Question 37

What type of interactions are important in protein/ligand complexes?

Answer 37

* Hydrogen Bonds * Ionic Interactions (salt bridges) * Metal Ion Ligation * Hydrophobic interactions * Cation-π interactions ## Footnote These interactions play a significant role in binding affinity.

Question 38

What is the role of a scoring function in docking?

Answer 38

To estimate protein-ligand binding affinity and guide the docking process. ## Footnote Binding energy is often calculated as Gibbs free energy.

Question 39

What is the outcome of a successful virtual screening?

Answer 39

Identification of compounds that fit the binding site and their binding strength. ## Footnote This process can involve automated pharmacophore searches.

Question 40

What does the case study on HIV protease inhibitors demonstrate?

Answer 40

The design of potent, bioavailable, nonpeptide cyclic ureas as inhibitors. ## Footnote It highlights the importance of specificity and molecular design in drug development.

Question 41

What is the main conclusion of the lecture?

Answer 41

Understanding pharmacophores, docking, and virtual screening is essential for successful drug design. ## Footnote These techniques help in the planning and synthesis of bioactive compounds.