Scientists apply a diversity of molecular alterations to progress an hit compound to a lead candidate. Scaffold replacement is a process in which a portion of the molecule could be replaced, or a group might be added to achieve a particular polar or steric interaction. In fragment-based drug discovery, fragments are usually needed to be extended or linked with a scaffold. Alfa Chemistry has developed various computational methods to accelerate these processes. We can improve the stability of the drug by replacing the scaffold that is prone to metabolism with a metabolically stable, low-toxic skeleton. And the pharmacokinetic properties can also be improved since the toxicity or adverse reactions of drugs are sometimes caused by the scaffold structure.
Figure 1. Sample scaffold replacement query. (Alain, D.; Elizabeth, S. 2007)
At Alfa Chemistry, we are able to perform scaffold replacement using the MOE's Linker pharmacophore features, in which two or more bond vectors are applied which are defined using Link pharmacophore annotations. Compounds can be directly bonded to the initial molecule when a sufficiently close superposition is achieved. We mainly use two modes to select the input ligand can for replacement:
1. Select scaffold in which the selected atoms are replaced.
2. Select R-group atoms in which the connecting atom of each retained R-group is selected.
Furthermore, we have combined CAVEAT style functionality with the MOE pharmacophore tool for 3D scaffold replacement. Our detailed scaffold replacement is as follows:
1. We firstly obtain the structure of the active site and a template ligand.
2. Then, our scientists use expert knowledge of the system or active site analysis tools such as ligand interaction diagrams, electrostatic maps, or contact statistics, to identify substituent locations.
3. We assign special pharmacophore features to preserve the bonds that link the scaffold with each substituent.
4. The excluded volumes are added to avoid clashes with the receptor and the substituents.
5. Additional pharmacophore features from key interactions present in the scaffold of the native ligand are also included.
6. We perform the searching of a database of candidate linkers and selecting optimal replacement scaffolds.
7. The novel molecule is formed by connecting the ligand and the R-groups.
Features of Our Methodologies
- Be used in conjunction with other query features, as well as volumes to create more sophisticated queries.
- Search any 3D conformation database.
- Combination of active site analysis tools and pharmacohpore-based scaffold replacement methods.
Alfa Chemistry's Advantages
- Our method can provide a simple-to-use interface that automatically creates complex scaffold replacement.
- We can provide additional filter services using molecular properties, pharmacophore, QSAR or fingerprint similarity models.
- Our experts can also refine and score the resulting molecules against any available receptor atoms.
Our salt/co-crystal screening services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!
- Alain, D.; Elizabeth, S. Ligand Scaffold Replacement using MOE Pharmacophore Tools. Chemical Computing Group Inc. 2007.