Theme 5 lecture 18 Flashcards
ligand based drug discovery
(5HT2C)
Generated using a catalyst at GSK.
3 models, all have selectivity and affinity.
With the software= hbond acceptors, ionisable groups, hydrophobic groups and aromatic rings.
Then the final product was superimposed.
Virtual screening
Look at slide 2 and 3 to understand the receptor sites, as well as the various bonds.
How quinolone binds differently and amide allows h1 interaction without blocking the s.
CoMFA/CoMSIA
Comparative molecular field analysis and comparative similarity index analysis
Graph is based on lennard-jones and coulomb potentials.
Potential energy V and R distance between atoms
Both atoms apart=no interaction
Closer together= d-d interaction s like VdW
Any increase or reduction in distance between 2 atoms will result in reduction in net attractive potential energy, because as atoms are pushed together unfavourable repulsive forces come into play due to overlap of atomic orbitals
Explain what properties of a compound which shows activity? look at slide 7
Measuresthe steric field and the electron field
longer chain=more electronegative and oxygen
Smaller groups= less bulk and less electron rich
e.g. benzene=delocalised pi system which is electron rich
Scaffholding
Physicochemical/pharmaceutical properties optimisation can take place by modification of areas OUTSIDE the pharmacophore (e.g. scaffold)
Structure Based Drug Discovery
Macromolecules and unbound
Ligand bound to macromolecule- direct visualization of ligand-targets.
Unbound macromolecule (apo)- ligand requires computational molecular docking into binding site.
Structure related macromolecule- requires generation of homology model of desired target before docking takes place
3D views
The view of ligand-target interactions allows the pharmacophore to be identified rapidly.
SBDD as enzyme inhibitors
Has been used with the design of the inhibitors
Addition of carbon units improved the H-bonding.
Incorporation of a carbonyl oxygen displaced the water, conferring entropic gains (why?)
Peptidic inhibitors bound via structural water.
This is because entropy is the measure of a disordered water system, and the binding of the carbonyl oxygen causes water to be disordered.
Looking at the X-ray structure, might it be wise to change the ether from a 3-pentyl to a larger alkyl group? Why or why not?
Right now, the 3-pentyl group is just the right size to have a beneficial interaction with Glu276.
It’s able to attract Glu276 in a way that helps the drug bind well to its target because of an “induced-dipole interaction.”
Glu276 repelling the larger non-polar alkyl group and thus the binding wil not take place
