Medicinal Chemistry Modifications

To elaborate on the possibilities to come up with new ideas in the context of medicinal chemistry modifications, we will dive into our drug design dashboard SeeSAR.

The first step in generating new ideas for compound transformations is to understand the complex of ligand and target structure. Either the ligand to be improved is already bound in the structure, or it must be placed into the structure via docking.
For docking, it is important to select the appropriate binding site and choose a binding mode of the ligand that ideally aligns with established SARs. In another scenario, we discuss how to proceed with this.

Once the working hypothesis is established, it's time to get into the details. Our HYDE algorithm makes it possible to identify dissatisfied regions within a molecule. These do not form sufficiently strong interactions within the binding site and therefore do not contribute favorably to the overall binding affinity. Small modifications to these individual heavy atoms can be made manually to observe their impact on the binding affinity.
Use SeeSAR's Molecule Editor Mode to modify your compound on a small scale.

Manually editing a structure is certainly possible for a small number of analogs to explore the effects on binding affinity. However, if you want to explore the chemical space around the compound more efficiently, you can use another tool.
In SeeSAR's Inspirator Mode, there is the 'Analoging' feature, which uses the MedChemesis engine: MedChemesis is a ligand mutation tool that takes the starting molecule and applies 290 of the most commonly used MedChem transformations to look for potentially improved analogs. The transformations include adding functional groups and heavy atoms, exchanging individual atoms in a chain or ring system, as well as converting motifs into their bioisosteric counterparts.

The fine-grained exploration of the binding site allows, among other things, the identification of positions for growth, as well as potential sites for H-bond interactions. Furthermore, it enables the generation of ideas for where lipophilic groups can be tolerated or even increase the ligand's affinity.

SeeSAR's Inspirator Mode also includes a core replacement feature, which uses the ReCore algorithm. The user first decides which parts of the molecule should be retained, thereby defining an area in the structure to be replaced. The algorithm then searches a 3D database for fragments that match the specified 3D vectors. The search is incredibly fast: hundreds of thousands of entries can be scanned in a matter of seconds for the best 3D alignment solution.

ReCore is ideal for campaigns where scaffold hopping plays a role or where rigidification of the compound is required. By additionally using pharmacophore constraints, the search can be adjusted and guided to further improve the quality of the results.

The extension of a ligand is a common method to introduce additional heavy atoms, functional groups, or entire ring systems, which can increase the ligand's affinity through additional interactions in the binding site. This method typically also introduces additional partners for H-bond interactions, which ideally even improve the solubility of the compound.

The growing functionality of SeeSAR's Inspirator Mode can be used to decorate a ligand in a desired position with fragments from your database or to replace an entire segment of the molecule with these fragments. The underlying FastGrow algorithm searches for the best shape-based conformation of the database fragments and attaches them to the desired location. Hundreds of thousands of fragments and their conformations can be searched within seconds for the best solutions.

Several databases with emphasis on different aspects of the drug discovery process are available as download.