Drug Discovery Services: Structure & Ligand-Based Design Strategies

The advantages of using structural information in drug discovery and design became apparent during the early days of protein X-ray crystallography (Blundell et al. l, 2006, https://doi.org/10.1098/rstb.2005.1800). The two classic examples include the discovery of the AIDS drugs Agenerase and Viracept, developed using the crystal structure of HIV protease (Lapatto et al. 1989, doi:10.1038/342299a0; Miller et al. 1989, DOI: 10.1126/science.2686029) and the influenza drug Relenza, designed using the structure of neuraminidase (Varghese 1999). However, at that time, most pharmaceutical companies were not convinced. They considered the method too expensive and time-consuming for industrial use, leaving the pursuit of structure-based drug discovery to academic groups. All this is history now, and the need for structural information in drug discovery is indisputable.
You may also view our article on how structural biology may help drug discovery.

Planning the services
At the start of a discovery project, we must examine the information available for the target in question. Based on this, we can design a possible strategy. The image to the right shows the combinations of available options:

  • Protein structure known / ligand known - structure-based drug discovery (SBDD) is straightforward.
  • Protein structure known / ligand structure unknown - de novo design.
  • Protein structure unknown / ligand known - use ligand-based drug discovery techniques.
  • Protein structure unknown/ligand unknown - fragment screening, high-throughput screening, etc.
These options are discussed below in more detail. However, you are welcome to contact us directly to discuss our services and to design the most optimal strategy for your project!
Strategies for structure-based drug discovery services
Before the drug discovery and design project starts, depending on the availability of structural data on the protein and its ligands, a project strategy needs to be defined. The image provides a short outline of different options. For details, please see the text on the left.

A blog post also provides a short discussion of strategies from hit identification to structure-based drug discovery.

Structure-based drug discovery & design

The most straightforward is the blue quadrant, when we know a ligand's and the protein target's structures and can apply structure-based drug discovery (SBDD). SBDD is, of course, the most time-efficient strategy. The bound ligand will allow the construction of a pharmacophore model to aid the application of computational methods, run virtual screening of fragment and/or larger compound libraries, and assess fragment/compound binding using docking methods. Our services also include an option to screen fragments or larger compounds using biophysical methods or our proprietary weak affinity chromatography (WAC™) technology.

When we identify hits, we can verify the details of their binding mode using structure determination of the protein-ligand complex by
X-ray crystallography or NMR spectroscopy. This also applies to virtual screening. Hit identification, lead optimization, and lead discovery will require repeated cycles of X-ray structure determination of the target protein with bound compounds. SAR (Structure-Activity Relationships) based methods are often very useful during the lead optimization process. Depending on the project's character, our services will be tailored for the most optimal and efficient performance.

Ligand-based drug discovery

The yellow quadrant corresponds to the case of ligand-based drug design. Here the ligand structure is already known (e.g., a substrate or an inhibitor), but the structure of the protein target is unknown. In this case, we apply a process called ligand-based drug design. The known ligand structure can be used to build a pharmacophore model based on ligand shape and electrostatics/polarity profile. This can filter a chemical library to include similar compounds and run QSAR analysis. One can also use computational chemistry methods for scaffold hopping and fragment replacement to generate new binders and, if required, even novel IPs. In the era of AlphaFold, it is also possible to use a predicted protein structure to generate a pharmacophore model to be used in virtual screening at the initial stage.

A known target structure will always substantially accelerate the drug discovery project. In the case of the yellow and pink quadrants, the best strategy would be to start with X-ray crystallography or NMR spectroscopy to determine the protein structure first, followed by determining the structure of a ligand complex. These methods are included in our services.

Known protein structure, no known ligand

The green quadrant represents the next best case. Here the protein structure is known, but no known ligand structure is available. Here we need to apply the principles of de novo drug discovery. Our services include computational chemistry and virtual screening, but we also can provide small fragment screening in combination with biochemical or biophysical assays to verify the binding. Once suitable binder/binders are identified, we can build a SAR model and determine the protein's three-dimensional structure in complex with the best ligands. One can then verify the binding mode, elucidate the interactions that stabilize the protein-ligand complex, and apply structure-based discovery and design methods.

De novo design: Fragment screening and hit identification

In fragment-based drug discovery and design (FBDD), our services provide two essential steps:

1. Fragment screening & hit identification
2. Hit to lead generation and optimization

The most straightforward strategy for de novo design (green quadrant) would be to run initial hit identification with FBDD methods. For this purpose, we primarily use our proprietary weak affinity chromatography (WAC™) technology. The screening can be run using our proprietary fragment library or clients’ libraries.

Compound activity assays are performed using the capabilities of our in-house partner Red Glead Discovery. As mentioned above, we may also assess the binding of the identified compounds using biophysical methods, like NMR spectroscopy, thermal-shift assay, or X-ray crystallography.

If no experimental structure is available for the target protein, SARomics Biostructures offers gene-to-structure services. In this case, the protein is cloned, expressed, purified, and crystallized, and its X-ray crystallographic structure is determined (see our learning center for details of the crystallography process).
protein X-ray crystallography services, gen-to-structure and off-the-shelf structures

X-ray crystallography

protein NMR spectroscopy services, fragment screening and ligand binding

Protein NMR spectroscopy

integrated drug discovery services

Integrated drug discovery

computational chemistry services, in silico screening and drug design

in silico lead discovery

Hit to lead & lead optimization

After identifying an active fragment (or fragments), further optimization of the interactions with the target protein and the physico-chemical properties of the molecules (hit expansion & lead generation) is made to obtain more efficient binders. This is substantially easier when the three-dimensional structure of the protein target is known. Multiple protein-ligand complexes and SAR modeling of the compounds provide detailed mapping of the binding site, which is used in designing new compounds. Hit-to-lead optimization typically requires several cycles. The result may be a series of compounds, which will generate the final lead after further optimization and testing.

At SARomics Biostructures, the service package, which includes hit-to-lead and lead optimization, is run in close collaboration with Red Glead Discovery.

The integrated drug discovery and structure-based drug discovery services at SARomics Biostructures are adapted to each project's needs and the customer's requirements.
Please do not hesitate to contact us to discuss your project.
antibody and antibody-antigen complex strucure, high order structure of biosimilars

Antibody and antibody-antigen complex structures

weak-affinity chromatography, fragment-based drug design

Weak-affinity chromatography