Lead Identification Flashcards
What is a lead compound?
a compound showing a property likely to be therapeutically
What is Teprotide and which drug is it a lead compound for?
it’s a peptide which was isolated from the venom of the Brazilian viper, lead compound for captopril
Give two endogenous compounds and name the drugs they are lead compounds for
Adrenaline and histamine. Adrenaline lead compound for propranolol and salbutamol, histamine for cimetidine
Describe the first stage of structure based drug design
step 1 (NMR based or X-ray based). NMR based – prepare sample of protein bound ligand, record high resolution 2D NMR spectra identify NMR signals and any inter-nuclear interactions to reconstruct the 3D structure. X ray – crystallise target protein then acquire structure by x ray crystallography
Describe the second stage of structure based drug design
download structure on computer for molecular studies, identify ligand and binding/active site, identify binding interactions between ligand and target by measuring distances between ligand and neighbouring atoms in binding site
Describe the third step of structure-based drug design
identify vacant regions for extra binding interactions / remove ligand from active site in silico / use receptor based virtual screening fit analogues into binding site to test binding capabilities / other approach involves rational de nova design
What does de nova design consist of?
identify interaction site, fit the appropriate fragments then bridging should occur
Describe the fourth step of structure-based drug design
identify the most promising analogues, synthesise and test for activity against target, prepare a sample of a selected ligand with target protein and record high resolution 2D NMR spectra
What does receptor based virtual screening involve?
involves docking of ligands from a large structural database into the AS of target, provided that the 3D structure of the target molecule is known from NMR analysis or X ray crystallography
What does virtual screening help us assess?
whether known compounds from large database are likely to be lead candidates for a particular target
Describe fragment-based design (NMR based screening) and its benefits
screens small number of compounds, hunts for low affinity binding fragments, identified fragments can be expanded to generate high affinity leads with high degree of chemical diversity. Adv- less resource intensive than HTS
Which isotopes are commonly used in NMR based screening
carbon 13 or nitrogen 15
In NMR based screening how can you identify the binding event
here will be a chemical shift of certain C NMR signals indicating binding event
