This is the second post in our series on structural biology and structure-based drug design. Before the start, I would like to thank all the people who supported the project on LinkedIn through your “likes,” by starting to follow our company, and by sharing the link with your network. Thank you very much! This was encouraging! I generally think that we need more science on LinkedIn. It also occurred to me that writing short popular science articles could be a good way for Ph.D. students to tell the world some exciting stories and market themselves as potential future employees. Together we could make science much more visible on LinkedIn!
In the previous post, I discussed the “when” question - when we need structural biology during drug discovery. Here I will discuss another question, which often needs to be answered before a drug discovery project starts, and this time it is a “what“ question. Assuming we have a target, what strategy do we need to follow at the beginning of the project? The answer depends on the essential information at hand. On the image, you can see what type of information I mean - it is the structure, of course:
1- the 3-dimensional structure of the protein target
2- the structure of a ligand
The general definition of “a ligand” refers to a molecule, most commonly a small molecule, that can modulate the target protein's function after binding at a particular site. The binding site could be an active site (substrate binding site) if the target is an enzyme, or it could be a co-factor binding site, an allosteric site, or a protein-protein interaction site.
Looking again at the image, we see four colored quadrants; inside each, we can read about the possible actions to follow.
Blue: known protein and ligand structures – here, we have all the advantages of structure-based design (SBDD); we can also do virtual screening, docking and scoring, and much more!
Green: known protein structure, unknown ligand structure – de novo design will be the starting point, and after identifying the first good quality binders, we can proceed with SBDD to get the method working to our advantage.
Yellow: known ligand structure, unknown protein structure – this is the so-called ligand-based drug design. Here we can run screening using, for example, a targeted compound library, build a QSAR model (quantitative structure-activity relationships, SAR like in SARomics!), create a pharmacophore model, and if we can find a reliable predicted model of our target, we could even run virtual screening.
Pink: protein and ligand structures are unknown – this is probably the most time-consuming (and costly) place to be at. In my opinion, it would be much more efficient to invest in determining the 3-dimensional structure of the protein target before proceeding with the project.
It is obvious where we want to be at the start of a drug discovery project, i.e., in the blue quadrant! Structure-based drug design allows us to leverage all the power of a 3D structure, thereby accelerating the drug discovery project and saving substantial costs.
The process of strategy choice in drug discovery is also discussed in our Learning Center. In the next post, I will discuss the following step, fragment/compound screening, which is followed by hit identification, hit expansion, and lead generation. As seen in the image above, screening is central to any discovery strategy we may decide to choose.
Follow us on LinkedIn if you haven’t done that yet, and stay tuned!