MSOP1016: Computational Methods in Medicinal Chemistry

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Questions and Answers

What type of properties can be mapped onto the surface of a molecule using colours in molecular modelling?

Physical properties only

Non-physical properties only

Both physical and non-physical properties (correct)

Chemical properties only

Which method in computational chemistry is known for its simplicity but less accuracy compared to quantum mechanics?

Molecular mechanics (correct)

Semiempirical methods

Quantum mechanics

Empirical force fields

What is the primary purpose of quantum mechanics in computational chemistry?

To estimate experiment results accurately (correct)

To calculate energy and kinetic forms of energy

To visualize non-physical properties of molecules

To map physical properties of molecules in colors

Which energy forms are considered for a penicillin molecule interacting with a penicillin receptor?

Both atomic vibration and electron motion Signup and view all the answers

What is the main difference between ab initio and semiempirical methods in computational chemistry?

Semiempirical methods are faster but less accurate Signup and view all the answers

In computational chemistry, what is the primary objective when calculating drug-receptor interaction energy at different positions (docking)?

Estimate the interaction energy between drug and receptor Signup and view all the answers

What is the main purpose of molecular dynamics simulations?

To track atomic positions and velocities at each step Signup and view all the answers

How does molecular dynamics handle the movement of each atom?

By breaking down dynamics to movements of each atom Signup and view all the answers

Why is it important for time intervals in molecular dynamics simulations to be small?

To simulate the fastest atomic motions correctly Signup and view all the answers

What is the main focus of a posteriori analysis in drug design?

Combining existing Structure-Activity knowledge with X-ray structure Signup and view all the answers

Which technique provides fast structural information and is done in a solution?

Multidimensional NMR Signup and view all the answers

What is the significance of expressing temperature in terms of atomic velocities in simulations?

It enables the simulation of molecular motion at high temperatures Signup and view all the answers

What is the main focus of Zanamivir bound in the active site of H1N1 influenza neuraminidase?

Identification of binding areas for drug molecules Signup and view all the answers

What is the typical duration of calculations for enzyme-ligands consisting of 20-30,000 atoms?

Several weeks Signup and view all the answers

In virtual drug screening techniques, what does chemoinformatics primarily deal with?

Balancing accuracy and time in methods used for biological behavior Signup and view all the answers

What is the disadvantage of X-ray crystallography compared to NMR in drug design?

Structure is not under biological condition in solution Signup and view all the answers

What is a key application of computational chemistry in drug discovery?

Designing a drug to interact with more than one target Signup and view all the answers

What method does not require information about the receptor in virtual drug screening techniques?

QSAR methods Signup and view all the answers

Which technique involves fitting analogues into the binding site in silico to test binding capability?

Virtual combinatorial chemistry methods Signup and view all the answers

Which process involves rational design of lead compounds based on the known structure of the receptor?

Structure-based drug design Signup and view all the answers

'Structure-based design' commonly requires knowledge of what to design drug molecules?

'Fit' target structure if known Signup and view all the answers

What was a significant result of random screening on all available substances during the HIV discovery phase?

Discovery of HIV protease inhibitors Signup and view all the answers

'Ca2+ channel antagonists and K+ channel activators' are particularly important for which therapeutic area?

Cardiovascular drugs Signup and view all the answers

'H-bonding interactions of an inhibitor of HIV-1 PR' is mainly focused on what aspect in drug discovery?

'Rational drug design' improvements Signup and view all the answers

'Drug repurposing - reprofiling - repositioning' is a strategy often used to:

'Discover new therapeutic uses' for existing drugs Signup and view all the answers

What is the main purpose of crystalising the target protein with a bound ligand in the structure-based drug design process discussed in the text?

To establish binding interactions between ligand and target Signup and view all the answers

In structure-based drug design, why is it essential to identify vacant regions for extra binding interactions?

To optimise lead compounds Signup and view all the answers

What is a challenge associated with designing drugs based solely on knowledge of the target binding site?

It may lead to unexpected changes in the binding site shape Signup and view all the answers

Which approach is suggested for designing drugs that interact with multiple targets in drug discovery?

Starting from a lead compound with activity against a wide range of targets Signup and view all the answers

Why is designing agents that interact with two or more targets advantageous in drug development?

It reduces the number of drugs needed to be taken Signup and view all the answers

What role does luck play in drug design according to the text's discussion?

It remains an important factor despite rational design approaches Signup and view all the answers

Why might logical step-by-step modifications not always lead to improved drug activity?

'Synergistic effects' might not be identified Signup and view all the answers

Study Notes

Molecular Dynamics Simulations

Used to simulate the behavior of a system
Breaks down dynamics into movements of individual atoms
Calculates velocities and forces acting on atoms using Newtonian equations
Tracks atomic positions and velocities at each step
Energy calculation is performed for each configuration using molecular mechanics

Molecular Dynamics Time Steps

Time intervals for calculations should be small enough to simulate fastest atomic motions
Example: C-H bond vibrations have a period of 10^-14 seconds, so time step should be around 10^-15 seconds (1 femtosecond)

Effect of Temperature

Simulation of molecular motion can be done at high temperatures to overcome energy barriers
Temperature is expressed in terms of atomic velocities

Typical Molecular Dynamics Studies

Simulation of a system of up to 500,000 atoms is possible
Typical enzyme-ligand systems consist of 20-30,000 atoms and take several weeks of computer time
Process involves:
- Building the target protein model from X-ray or NMR results
- Adding the ligand and immersing it in a box of water or applying a dielectric constant
- Performing energy minimization to relax the initial molecule
- Heating the system to the required temperature
- Performing calculations for 250 picoseconds to 25 nanoseconds with a sampling time step of 1 femtosecond

Processing of Results

Find the lowest-energy binding mode
Track interatomic distances between residues of interest
Calculate properties, such as free energy of binding

Virtual Drug Screening Techniques (Chemoinformatics)

Deals with a massive amount of molecules for their biological behavior
Methods include:
- Drug-receptor docking: calculating interaction energies between ligands and the protein
- Ligand-based methods: QSAR or pharmacophore-based methods
- Virtual combinatorial chemistry methods: designing a diverse set of molecules for screening

Computational Chemistry

Required for accurate modeling of molecular behavior
Properties should be calculated and assigned
Theoretical model should accurately estimate or reproduce experimental results

Molecular Modelling

Offers techniques beyond traditional graphs
Visualizes molecular properties, such as:
- Mapping positively charged parts with red and negatively charged parts with blue
- Hydrophobicity
- Non-physical properties, such as conservation of residues or similarity to other proteins

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Description

Test your knowledge on computational methods in medicinal chemistry with this quiz based on Dr. A. Edwards' lecture 7 from MSOP1016 at Medway School of Pharmacy. The quiz covers topics like drug discovery, drug design, and the role of computers in medicinal chemistry.