Enabling rational, accelerated 4D structural drug design using experimental rather than theoretical data

The importance of drug 3D-shapes

Drug molecules ameliorate diseases by binding to target proteins to modulate their biological function. The 3D-shape information of the binding interaction often available during a drug discovery programme is illustrated in the figure below, using the drug lisinopril (Prinivil®) and its target angiotensin-converting enzyme (ACE). For particular classes of proteins, X-ray crystallography is routinely available to support drug discovery projects by providing experimental 3D-information on both the free and bound states of the protein.

ligand protein binding interaction

While the importance of the 3D-shape of both free and bound protein targets is well recognised and routinely used in structure-based drug design (SBDD), the critical role of the 3D-shape of the free ligand is generally overlooked.

For a drug ligand to bind strongly to its target and have a strong effect, it needs to be able to adopt the right shape to fit into the target binding site. If a molecule has to dramatically change shape to bind to its target, it is likely to bind poorly and therefore be unsuitable as a drug. In contrast, if a molecule is already the right binding shape (the ‘bioactive conformation’), it is more likely to bind strongly to the target and be a good drug. Knowledge of the 3D-shape of the free ligand is therefore extremely valuable in guiding the design of the best drug molecules.

In conventional drug discovery, the shape of the free ligand is not known, so the majority of early-stage drug discovery efforts involve iterative medicinal chemistry synthesis and testing of molecules, gradually improving both the ligand’s shape and charge properties until a molecule is found that binds tight enough to the target. To make matters worse, for many important target classes (e.g. GPCRs, ion channels), 3D-shape information is usually unavailable for the proteins, so not only is the starting shape of the ligand unknown, but also the bound shape the chemists are seeking is unknown. This all leads to an expensive, time-consuming process in which the solution is found after a large amount of trial-and-error, if at all.

The Conformetrix proprietary technology platform allows the 3D-shapes of free ligands to be precisely measured from experimental data, meaning that medicinal chemists no longer need to work in the dark. In cases where protein 3D-shapes are available, comparison between free and bound ligand 3D-shapes immediately highlights the exact areas of the molecule that the medicinal chemist needs to address to redesign the drug molecule to be the right shape. In cases where there is no protein 3D-shapes, comparison between multiple ligand 3D-shapes also provides clear direction and decision-making for the medicinal chemist. Moreover, other problems such as cell permeability, metabolic liabilities and off-target effects can all be overcome using ligand 3D-structures.

If you would like to know more about the importance of solution state free ligand 3D structures and how they can be used to transform the medicinal chemistry workflow please read our article 'Measurement, Interpretation and Use of Free Ligand Solution Conformations in Drug Discovery' in Progress in Medicinal Chemistry.