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? To answer this question we first need to look at the whole process. It is highly interdisciplinary, and different scientific disciplines are required at different stages. Thus, for target identification we need molecular & cell biologi, immunology, structural biology, etc. The next stage is hit identification and lead discovery, that includes lead generation and optimization. Here we need a lot of chemistry of course, 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 mostly required at the early stages of the process, that is, 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 normally 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 useful. Lead optimization involves the improvement of the pharmacokinetic properties of the ligand by optimization of 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, nowadays essentially all large pharma companies have in-house structural groups, and several service companies (contact research organizations, CRO), like SARomics Biostructures, have emerged.
Time is money, and structural biology tools have become essential in the acceleration of the drug discovery process. 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 improv 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.
In the following posts I will go into details of the methods and give some illustrations. At some moment I will disclose what SAR in SARomics actually means.
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Blundell et all. (2006). Phil. Trans. R. Soc. B 361, 413–423