Design and optimization of the chemical structure of a drug based on the structure of its biological target.

Increasingly, structural information is available for proteins (e.g., Protein Data Bank) identified as potential drug targets. This often includes insight into the active site of the target. Structure-based drug design (SBDD) uses computational chemistry tools in which the structure of a protein is used as the basis to identify or design new chemical compounds that could bind to the target resulting in inhibition of the target protein. The site of the protein that is targeted is referred to as a binding site, defined by the surrounding amino acids. When compounds are computationally made to “fit” the binding site, this is often referred to as molecular docking. This calculates the conformation and orientation (or so-called “docking pose”) of compounds at the targeted binding site. A variety of scoring criteria is used to predict the most likely stable interaction and to design or select the best compounds for testing against the target protein experimentally. These experimental results will support further rounds of SBDD by gaining an understanding of how the designed structural changes alter the biological activity or structure-activity relationship. A co-crystal structure of the best binder within the target protein can confirm the computationally predicted interactions between the molecule and the target protein.

SBDD encompasses a range of applications. In structure-based virtual screening, a larger number of compounds can be screened first computationally to find hits addressing the selected binding site of the protein. The best virtual hits can then be tested experimentally. By contrast, structure-based de novo drug design is based on the piecing together of molecular subunits to create compounds predicted to fit into the selected binding site.

Molecular dynamics simulations model the behaviour of complex molecular systems based on the fundamental properties of chemical entities and interactions between them, providing a more dynamic view of interactions between compounds and their targets for SBDD.