Question 3: What do you think is the most efficient drug discovery method?

Apr 7 • Clinical Research Associate, Clinical trail, CRA certification, cracertification_Q&A, cracertification.co.uk • 2299 Views • Comments

Question 3: What do you think is the most efficient drug discovery method?

Introduction There are several methods by which one can get information about the proteins. Different methods are related to different types of information. We can think to e.g. the gel filtration or Western blotting where we obtain information from the macroscopic level of the protein (size, molecular mass, binding to an antibody etc.). One may find information about the proteins with several chemical modifications (or even mutations in the DNA – e.g. site-directed mutagenesis) and checking what kind of change occurred one could draw a conclusion for the structure (e.g.: active center prediction – with the investigation of substrate-specificity – , side-chain properties etc.). These experiments lead us closer to the real structure, but we could not be informed enough for being sure that different subunits how are arranged into a 3D construction. And we do not know from this level of examinations lots of different sorts of information needed to predict the whole structure and the way of the mechanism by which it is working (e.g. as an enzyme).

On this deeper level we need methods refered to the smallest parts of the structure. This level is the atomic or even the electron level. Now, we have some suitable methods which are capable to resolve these levels for example NMR and  X- ray crystallography.

I think among all drug discovery methods NMR is the most efficient drug discovery method because NMR offers some unique features that make it an attractive alternative for applications in drug research as compare to others. The primary, intrinsic advantage, however, is the ability to detect weak intermolecular interactions, e.g. between a ligand and a target, with unmatched sensitivity. This ability makes NMR ideal for fragment-based screening. In a fragment-based approach, comparably small and simple molecules are screened for binding to a target. These compounds often reveal only a weak affinity. However, when several fragments for different binding sites of the target are identified, they can be linked to form higher affinity ligands. Although the linkage of fragments is an additional difficulty, this approach accesses a larger structural space because each fragment can be optimized separately.

In contrast, structural space is significantly restricted in conventional high throughput screening (HTS), in which the identified hits often are hydrophobic and possess relatively high molecular masses already, and it is difficult to improve their activity without further increasing either their hydrophobicity or molecular weight, or both.

 

Advantages of NMR:

1. Several types of information from lots of types of experiments

2. They obtain angles, distances, coupling constants, chemical shifts, rate constants etc. These are really molecular parameters which could be examined more with computers and molecular modeling procedures.

 3. If we have enough strength of the magnetic field (the resolution is the function of that) than we can handle all of the atoms “personally”

4. With a suitable computer apparatus we can calculate the whole 3D structure

5. There are lots of possibilities to collect different data-sets from different types of experiments for the ability to resolve the uncertanities of one type of measurements

6. The motion of the segments (domains) can be examined

7. This method is capable to lead us for the observation of the chemical kinetics

8.Thermodinamic (and certainly kinetic) data could be determined from a well-prepared (dynamic)NMR experiment

9. We can investigate the influence of the dielectric constant, the polarity and any other properties of the solvent or some added material

A further key advantage of NMR is its ability to provide additional structural information, which is welcome even at the earliest stages of the drug development process. Structural information supports rational lead design or the design of biased libraries based on known structure activity relationships (SARs).

The number of compounds that can be screened by NMR is limited to about 103–104 depending on the technology used – much lower than for HTS and in silico screening methods (105–106compounds). Hence, it is not the number of compounds that makes NMR an attractive method, but rather the possibility to use fragment-based screening. In combination with the structural information that can be extracted simultaneously, NMR experiments can open up new, unexplored regions of chemical diversity in the search for drugs.

 

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