force field
functional form and parameters set to describe the potential energy of a molecular system
Ep of system
energy of a system is considered to have due to the positions of its components in space
simple force field
bond stretching angle bending torsion electrostatic van der Waals
bonded terms
bond stretching
angle bending
torsions
non-bonded terms
electrostatic interactions
van der Waals
electrostatic interactions
non-uniform charge distribution in a molecule, represented by fractional point charges
van der waals
attraction due to dispersion
repulsion due to exchange replusion
Lennard-jones potential
Lennard-jones potential
sigma - where passes through 0 on x
e - well depth
equilibrium distance when = minimum
deficiencies in point charge model
lack of polarisability as charges not affected by the local electrostatic environment
polarizability
modification in the charge distribution in an atom due to an applied electric field
water models
set parameters used fro models water or aqueous soltions
water molecules rigid
fixed bond length, angle and torsion
only account for non-bonded interactions
3-site. model
charges on atom
4-site model
charges on atom and one charge away from o
5-site model
2 lone pairs with. charge
6-site model
2 lon e pairs and charge away from o
more accurate models of water
intramolecular flexibly
including polarizability
potential energy surface
energy of the molecular system as a function of the nuclear coordinates
potential energy surface
maxima - eclipsed
minima - staggered
transition state
energy minimisatuon
minimum energy ofd a paerticujkar molecule
calculate energy at particular bond length, change bond length and measure new energy
molecular dynamics
form of computer simulation where the atoms and molecules are allowed tov interact with eachothetr for a period of time
phase space
define the state of a molecular system containing N atoms, 6N values are required 3 coordinates x,y,z and 3 momentum components px,py,pz per atom
calculate tranjectory
have energy function
differentiate -dv/dx = force
newtons 2nd law to give a = f / m
integration of equations of motion give v and x
gives trajectory describing how x,v,a of particle vary with time
particles experience a constant force
charged partible through uniform electric field
force on particle is not constant
running an md simulation
establish initial configuration of system assign initial velocities calculated the force on each atom and new positions of atoms equilibrium phase production phase
md used to
stimulate a reaction
calculate thermodynamic properties
ensemble
collection of points in phase space, a collection of the mictrostates in the trajectory
calculate thermodynamic properties
statistical mechanics
macroscopic property calculated as an average over a corresponding microscopic property
microanonical ensemble
thermally isolated system - constant E, N, volume
canonical ensemble
system exchanges energy with heat bath. temp constant, n and volume
lead compound
molecule with pharmacological or biological activity can be used as a starting point for chemical. modicifaqtion to enhance its potency and selectivity
agonist
enhance or normal activity as natural substrate
antagonist
inhibits the effect of natural ligand
inverse agonist
creates opposite of natural ligand
drug activity
molecular binding of one molecule to the pocket (binding site) of anothwe
docking
predict structure and stability of complex, formed by 2 interacting molecules ligand and protein
search alogorithm
generation of plausible strujcutres
scoring function
how strong it binds
calculate likelihood that the pose represents a favourable binding interaqction
a good scoring function is
selective - distinguish between correct t and incorrect structures
efficient - fast
search algorithms
protein and ligand rigid bodies (6 degrees of freedom)
ligand flexible
both flexible
QSAR
quantitive structural activity analysis
method that relates numerical properties of a drug molecule to its biological acitivty
receptor flexability
bond lengths/angles do not affect there shape of molecule much - torsions
qsar
v = f (p)
pharmacophores
set of structural featured that is common to a series of active molecules, recognised by receptors and are responsible for drug activity
pharmacophores - structural featrurws
h bond donors and acceptors, charged groups, aromaticity, hydrophobic groups
3d pharmacophore
includes spatial relationship between pharmacophoric groups. relationships expressed as distances, torsio ns and angles
pharmacophoric mapping
can determine 3d pharmacophoerws for a series of comppununs
assumes all active compounds bind in similar way
de novo ligand design
design of new molecules
