pharmacophore determination for a hit or lead series

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Once the discovery group has identified a pool of hits – these are hits with confirmed potency on the target, some of the hits will be further explored and modified in structure to determine what structural features are required to achieve on-target activity. These studies determine the structure-activity relationships of the compounds – also called SAR. SAR is a fundamental idea in drug discovery. The chemical structure of a compound affects its biological activity. Understanding a compound’s SAR is vital because it opens the door to improving the observed activity of a compound through changes to its structure.
Let’s assume the compound in the middle of the slide is one of our hits. Compounds are often described based on their scaffold, which is the core structure of a molecule. The scaffold normally includes rings in the molecule and any connections between the rings. In this case, our hit is a 3-phenylpyridine. The 3-phenylpyridine scaffold displays different functional groups, such as the carboxylic acid and methoxy group, for interaction with the target. Based on this hit, other compounds may be synthesized to better understand what features are required for target binding. The new compounds may have the same scaffold or a different scaffold. Note that the structure in the upper right is missing the ring nitrogen and has a biphenyl scaffold. The collection of compounds represents a hit series. So our hit has grown from a single molecule to a series of related compounds.
With a set of active compounds, the structure of a molecule can often be reduced to its essential features for binding – the essential structure required for activity. This is again an example of SAR. On the left is a member of the hit series that has three key features – an H-bond donor in the alcohol, an H-bond acceptor in the pyridine nitrogen, and a hydrophobic or lipophilic group with the ethoxy group. From these relationships, the model of a pharmacophore can be constructed. The model is very often generated with software that may also incorporate structural information on the drug target. The pharmacophore describes just the key features of the target binder and distances between the features. What can we do with this pharmacophore model?
Generating a pharmacophore model helps the discovery team identify additional molecules that are also similar to the pharmacophore model and are therefore likely to bind to the target. By predicting on-target potency, we can also presumably predict efficacy as well. Furthermore, the pharmacophore model can reveal sites of a molecule that might be modified to tune other properties, like solubility, membrane permeability, and maybe target selectivity. For example, based on our pharmacophore model, this part of the aromatic ring is not critical for target binding. If we need to change the solubility of this molecule, we might try making changes to this part of the molecule rather than the parts that are vital for target engagement.