People often ask about what our company, SARomics Biostructures, does. For us who work within the field, it is sometimes easy to forget that other people may not know so much about the details of what we do. We need to explain this more often, and this text is an attempt to do just that, to start a project to give our followers and all those interested in the subject an idea about the general principles of structure-based drug design. In future posts, I plan to describe in more detail and compare the experimental methods we apply in our work.
Let us first start with “when.” When do we need structural biology in drug discovery and design? We first need to look at the whole process to answer this question. It is highly interdisciplinary and requires different scientific disciplines at different stages. Thus, for target identification, we need molecular & cell biology, immunology, structural biology, etc. 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, and in addition, structural biology, pharmacology, toxicology, etc. The following stages include candidate drug generation and registration, followed by different phases of clinical studies, and finally, drug registration and marketing.
Structural biology is mainly required during the process's early stages: hit identification, lead optimization, and lead discovery. A “hit” is a molecule with some degree of activity towards the target, identified during an initial small molecule compound library screening (hit identification). This molecule typically needs to be modified in multiple cycles (lead generation) to reach a compound with better activity parameters (lead discovery). This is the stage at which structural biology and 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