Lead Optimization

Lead Optimization into a Drug Candidate

Once a promising hit compound is identified, further optimization is essential to enhance its potency and selectivity, thereby minimizing potential side effects.

During the subsequent lead optimization phase, analogs of the hit compound are synthesized to achieve nanomolar potency or better. To streamline this process and reduce costs, rational design and careful selection of compounds for synthesis are crucial.

Exploring Structure-Activity Relationships

In order to improve the potency of a compound, interactions between the target structure and the binding molecule need to be improved.
This can involve the introduction of new functionalities into the molecule to fill yet unoccupied cavities or the removal of groups that do not contribute to the overall binding activity favorably. It is also possible to exchange smaller sections of the molecule or even single heavy atoms to boost the activity of a compound.

Medicinal chemists can come up with ideas for small modifications at the compound to explore the structure-activity relationships (SARs) in small portions to continuously improve the potency of the compound.

Exploring the Chemical Space around a Compound

While smaller molecule modifications allow a fine-grained exploration of SARs using analogs—the most commonly applied strategy in lead optimization— it limits opportunities for innovation and novelty.
More drastic approaches replace larger parts of the molecule with the aim to discover different decorations and core motifs of the template molecule while maintaining the important interactions with the target's binding site and complementing the cavity. Guidance by pharmacophore constraints further enhances the quality of the results allowing the screening for ligand-unbiased bioisosteric motifs.

BioSolveIT software for lead optimization:

SeeSAR: Visual, drug design dashboard for computational and medicinal chemists.
The Molecule Editor Mode is your place to modify your ligand and explore the effect of your changes on the ligands binding affinity. The visual feedback provides you with feedback on how good your idea was and which area of the compound to improve.
The largest feature compartment for lead optimization within SeeSAR is the Inspirator Mode.
Within the Inspirator Mode it is possible to generate ideas of small modification around your compound applying common medicinal chemistry transformations (MedChemesis), replace core parts of the molecule with motifs fitting the 3D arrangement (ReCore), or to screen hundred-thousands of decorations within seconds to discover novel ideas how to complement the binding site (FastGrow).

Command-line tools for lead optimization:

FastGrow: Fast and efficient exploration of decorations to complement a binding site.

Ligand-Based Lead Optimization

The lack of information on the target's structure or uncertainties about the binding mode of the ligand can impede structure-based drug design mentioned above.
In those cases, ligand-based approaches bypass the 3D requirements and enable focused lead optimization.

By systematically purchasing or synthesizing analogs of a compound with varying decorations and subsequently assessing their biological activity, SARs can be established step by step. The commercial availability of these analogs determines how quickly insights can be gained. The more relevant analogs available, the faster the series can be explored and developed. Accordingly, the potential of a compound collections increases with its size and comprised analogs to a molecule of interest.

Chemical Spaces are ultra-large compound collections of accessible compounds. Taking the "SAR by catalogue" concept into the Chemical Space world, "SAR by Space" emerges as an efficient method to profit off the huge numbers of commercially available compounds.

BioSolveIT software for analog mining:

infiniSee: Chemical Space navigation platform with a graphical user interface.
With its Analog Hunter and Motif Matcher Modes, infiniSee searches for related compounds inside ultra-large Chemical Spaces to your query compound. Respectively, it screens for similar compounds based on molecular fingerprints and the maximum common substructure which both can be considered as valid methods to retrieve analogs.
infiniSee xREAL: Exclusive platform to screen Enamine's largest compound catalog featuring trillions of compounds.

Command-line tools for Chemical Space exploration:

SpaceLight: Retrieves close analogs based on molecular fingerprints. Algorithm behind the Analog Hunter Mode.
SpaceMACS: Performs maximum common substructure searches, as well as exact substructure mining. Algorithm behind the Motif Matcher Mode.

Additional Considerations

When picking analogs for synthesis or purchasing, keep the chemical diversity in mind. It is better to explore a broad range of functionalities to cover a larger area of the Chemical Space. Focusing on particular parts of the molecule is always possible if required.
Keep an eye on the physicochemical and ADME properties during planing of the next steps.
Use pharmacophore constraints during ideation to collect proposals for potential bioisosters. "Ring system" constraints can help you to rigidify your molecule.
In order to include selectivity aspects into your design, align the binding sites of your targets with other members of its family and its off-targets. Also dock your compound into the respective aligned binding sites for insights.
Endogenous ligands typically are accompanied with a series of reported analogs that help you establish SARs and identify important interactions. Check for literature to enhance your data set.

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Lead Optimization