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Medicinal Substances > Molecular Modelling > Flashcards

Molecular Modelling Flashcards

1
Q

What is molecular modelling?

A

Studying a molecular structure and function through model building and computation

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2
Q

What can we do with molecular modelling?

A

*study ligand-protein interactions
*look at protein folding
*drug design
*calculate molecular properties

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3
Q

What does molecular modelling involve?

A

*molecular graphics
*molecular dynamics
*molecular mechanics
*QSAR
*homology modelling
*molecular docking
*quantum mechanics
*free energy calculations

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4
Q

What is molecular mechanics?

A

*the root of molecular modelling
*molecules rotate, vibrate and translate to assume favoured conformations as a response to inter and intra molecular forces acting upon them
*energies known as FORCE FIELD- derived from experiment and quantum mechanical calculations

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5
Q

What is the equation for force fields?

A

Energy = Ebonded + Enon-bonded

*Ebonded= Ebond-stretch + Eangle-bend + Erotate-along-bend
*Enon-bonded= Evdw + Eelectrostatic

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6
Q

What is a molecular graphics?

A

Different graphical visualisation of molecules
*wire frame
*stick
*ball and stick
*space filling

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7
Q

How can proteins be represented on a computer?

A

*C- alpha, trace like
*ribbon like
*cartoon like

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8
Q

How are positively charged and negatively charged residues shown?

A

*positive = blue atoms
*negative= red atoms

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9
Q

How are hydrophobic residues shown?

A

Pink spheres

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10
Q

How is protein structure determined using x ray crystallography?

A

*X- ray crystallography
*determines atom arrangement within protein crystal
*ray beams strike crystal and diffract into many directions
*angles and intensities of diffracted beams produce 3D image of ELECTRON DENSITY
*from electron density, MEAN POSITION of atoms determined- and chemical bonds

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11
Q

What is a new method being experimented by scientists for use to determine protein structure?

A

Cryo-electron microscopy
Used for larger molecules

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12
Q

What is a disadvantage of x ray crystallography?

A

Protein must be small and in a crystal form

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13
Q

What are examples of non computational methods to determine protein structures?

A

*x ray crystallography
*cryo- electron microscopy
*NMR
*protein data bank

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14
Q

What is the computational source of protein 3D structures?

A

*homology modelling
*constructs atomic resolution model of target protein from AMINO ACID SEQUENCE and experimental 3D structure of related homologous protein- template
*if no similarity to another protein- use Ab initio modelling

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15
Q

How do we know what the most stable confirmation of a protein is?

A

Generate different conformations and compare their steric energy
Using molecular dynamics

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16
Q

What is molecular dynamics?

A

*Computational method that describes equilibrium and dynamics properties of biological systems
*using newtowns law of motion
*info generated at microscopic level- atomic position and velocities
*CONNECTS STRUCTURE AND FUNCTION- additional info than nmr and x ray crystallography provides
*help find most stable confirmation

17
Q

What can molecular dynamics be used for?

A

*protein stability
*conformational changes
*protein folding
*molecular recognition ie proteins , DNA
*drug design- use of multiple conformations to study ligand-protein interactions

18
Q

Why use computer modelling?

A

*most models too complicated for purely theoretical reasoning
*numerical experiments need accuracy- computers fast enough

19
Q

What are the overall sources for 3D structures- computational and not?

A

*nmr
*X-ray crystallography
*homology modelling

20
Q

Two facts about changed residues in proteins.

A

*stabilise N and C terminus
*occur on surface or in active sites

21
Q

What does X on the molecule stability graph mean?

A

*local energy minimum

22
Q

Why is energy minimisation used?

A

To find stable confirmation for molecule

23
Q

What is a pharmacophore ?

A

*area of binding which is common to various ligands which bind to it

24
Q

How can you find a pharmacophore?

A

*download a protein-ligand complex to computer and identify molecular interactions that hold ligand into binding site
*group positions can then be mapped to produce a pharmacophore

25
Q

What are the advantages of ligand based drug discovery?

A

*very fast to screen large chemical databases
*method works well- finds ligands

26
Q

What are disadvantages of ligand-based drug discovery?

A

*what if molecule binds to different sites?
*flexible molecules require you identify correct active conformation

27
Q

What are the methods used for computational drug discovery?

A

*ligand-based discovery
*structure-based discovery

28
Q

What are the three things needed to carry out a structure based drug discovery?

A
  1. Structure of the protein
  2. Computer representation-library
    3.algorithm that predicts how molecule binds and how strong - MOLECULAR DOCKING
29
Q

What is molecular docking?

A

Used in structure based drug discovery- study of how two or more molecules fit together
Molecules can be moved within binding site to identify favourable confirmation

30
Q

What are the two directions of structure based drug discovery?

A

*De novo design- constructing new ligands to fit into binding sites
*virtual screening of molecular libraries -to find ligands to fit into binding sites

31
Q

What two methods are used in de novo design of drugs?

A

*link method- fragments placed into active site in favoured way and linked into one molecule
*grow method- one single fragment placed into active site and grown into a molecule

32
Q

What type of fitting should be used in de novo design?

A

Loose fitting

33
Q

What drugs were achieved by structure based design?

A

COX-2 inhibitors

34
Q

What are advantages of structure based design?

A

*structures are in 3D- structure can be manipulated to be seen from any angle, binding sit can be enlarged
*small molecules can be docked into various regions to determine their fit

35
Q

What are limitations of structure based drug design?

A

*coordinates of nmr and x ray crystallography required
*uncertain of exact position of each atom (2-2.5A)

Medicinal Substances (19 decks)

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