The image indicates that the first 3 stages of the drug discovery process require structural information. 1) Target identification & validation
- protein three-dimensional structure is required in the study of the protein in question, e.g. the location of substrate binding site (or sites), its reaction mechanism, evolutionary relationships, etc.2) Hit identification / lead generation
- here, together with computational chemistry, medicinal chemistry, biochemistry, etc., structural information will contribute to a considerable acceleration of the drug discovery process.3) Lead optimization
- at this stage the structure of the protein will be of great help in mapping the interactions made by the tested compounds and in planning subsequent optimisations of compound parameters.
It is also clear from the image that the drug discovery process is highly multidisciplinary and requires expertise in a broad range of sciences. Planning a structure-based drug design project
Before starting a structure-based lead discovery project some general considerations need to be made. We assume that the protein target has been identified and verified. Since our aim is to identify a small molecule compound that will bind to the protein and somehow modulate its activity, it is preferable that the protein is well studied in the lab. For example, if it is an enzyme, it would be a huge advantage to have a good idea about the type and mechanism of the biochemical reaction catalyzed, the availability of inhibitors, co-factor requirement, the need for an allosteric regulator, presence of metals, etc.
For structure-based drug design a high resolution three-dimensional structure of the protein is a requirement, either from Protein crystallography, NMR spectroscopy or cry-electron microscopy. The resolution of the structure needs to be at least better than 3 Å, but preferable 2.5 Å and better. As mentioned earlier, the higher the resolution the more accurate the structure
will be, and the more accurate our description of ligand-protein interactions will be.
Generally, the drug design process is repetitive. The hits initially identified
against a small-molecule compound library will normally need to be optimized in a number of cycles until we have a so-called lead molecule (a process called lead discovery & lead optimization
). If a fragment library used for screening, after hit identification we will enter a process called hit expansion
, described later in the chapter. The aim is to identify drug-like molecules, with stable binding, good solubility, low toxicity that would also be not very expensive to synthesise.
In a case when known inhibitors of the enzyme already exist (a good place to look for those can be the PDBe Chemical Components Library
), the structures of the inhibitors in complex with the protein can be used for mapping the interactions within the binding site and for build a so-called pharmacophore model
for the binding site. Such models can be used, among other things, in filtering compound libraries
before screening for potential binders. Obviously, there is no meaning in including in the library compounds that would not fit into the protein binding site, for example, due to bad shape complementarity, absence of groups which would interact with the binding site amino acids, etc.
If there is no experimental three-dimensional structure available for the protein target one could try to find a homologous protein with a known three-dimensional structure, which may subsequently be used as a template for homology modeling. This may help at least at an initial stage.
We should of course remember that the structural part, even if it is important, it is a relatively small and cheap part of a drug discovery project. The main ideas presented on this page are discussed in more detail on the following pages.