This post attempts to answer a question we often hear, why do we need a structural biology services company? Here I will answer the question by briefly discussing the general principles of applying structural biology to structure-based drug design. In future posts, I plan to discuss the experimental methods we use in our work in more detail.
First, we must examine the whole process to understand how structural biology contributes to drug discovery. Structural biology and drug discovery are highly interdisciplinary and require different scientific disciplines at different stages, as seen in the schematic image above. For target identification, we need, e.g., molecular & cell biology, and immunology, although structural information is also quite valuable at this stage, for example, for understanding the function of the potential drug target, and its drugability. The next step is hit identification and lead discovery, which includes lead generation and optimization. Here we need a lot of chemistry, like computational chemistry, synthetic & medicinal chemistry, biochemistry, pharmacology, toxicology, etc., and of course, structural biology. Later stages include candidate drug generation and registration, followed by clinical studies, and finally, drug registration and marketing.
Structural biology's central role is during hit identification, lead generation, and optimization. A “hit” is a molecule with some degree of activity towards the target, identified during a small molecule compound library screening (hit identification, discussed in a later post). The hit molecule must typically be modified in multiple cycles (lead generation) before it becomes a compound with better activity parameters (lead generation). This is the stage at which structural biology and structural bioinformatics are most helpful. Lead optimization involves improving the ligand's pharmacokinetic properties by optimizing such parameters as absorption, distribution, metabolism, excretion, toxicity, etc. Of course, even here, structural biology can be of great help.
In a small review paper published in 2006, Tom Blundell, one of the pioneers of the application of X-ray crystallography to drug discovery, wrote that in the early days of X-ray crystallography, pharmaceutical companies did not want to put money into structural methods because they thought that it was “too expensive and time-consuming to bring in house.” However, all large pharma companies nowadays have in-house structural groups, and several service companies (contract research organizations, CRO), like SARomics Biostructures, have emerged.
Time is money, and structural biology tools have become essential in accelerating drug discovery. The ability of the structure to reveal details of the interactions of ligands with the binding site of the target provides direct insights that help improve the design of compounds. This is what we do at SARomics Biostructures. A recent blog post provides an overview of different structure-based drug discovery strategies.
I will detail the methods in the following posts and give some illustrations. At some moment, I will disclose what SAR in SARomics means.
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Blundell et all. (2006). Phil. Trans. R. Soc. B 361, 413–423