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SBDD (Structural Based Drug Design) - Coggle Diagram
SBDD (Structural Based Drug Design)
First cycle (HIT FINDING)
X-ray, NMR
Compounds are placed in selected regions of the target using using computer algorithms
Test by biochemical assays
Second cycle (H2L)
Structure of the target in complex with a hit-lead from the first cycle
Several additional cycles
Synthesis of optimized lead
Structure determination of the new complex
Optimization of the lead compound
1. TARGET PRODUCTION
Design of protein fragments
Design of primers
Parallel cloning
Microscale expression in suitable strains
Solubility tests
Small scale expression in cells and solubility tests again
Upscale and protein purification
Protein characterization
Large scale protein production
2. X-RAY CRYSTALLOGRAPHY
Prerequisites
10 mg of purified protein
Homogeneous
20 mg/l of concentration
Stable
Approaches
Batch (and micro-batch) experiments
Vapour diffusion
Crystallization robots
3. NMR
Kinds of data
Chemical shift data
Integrals
H-H coupling
Physical parameters
Chemical shift
Relaxation parameters
Dynamic parameters
Diffusion coefficients
Saturation transfer difference (STD)
Transfer NOE
ADVANTAGES AND DISADVANTAGES USING X-RAY AND NMR
ADVANTAGES
X-RAY
: no size limit, structures can be very precise, faster
NMR
: don't have to grow crystals, look at dynamic processes, determining the structure of the protein in solution, detects multiple conformations
DISADVANTAGES
X-RAY
: you have to grow crystals, electron density is the average for molecule in the crystals over the time of data collection, structure may be influenced by crystal lattice
NMR
: size limit, structure less precise