Impact of Linker Strain and Flexibility in the Design of a Fragment-Based Inhibitor
The linking together of molecular fragments that bind to adjacent sites on an enzyme can lead to high-affinity inhibitors. Ideally, this strategy would use linkers that do not perturb the optimal binding geometries of the fragments and do not have excessive conformational flexibility that would increase the entropic penalty of binding. In reality, these aims are seldom realized owing to limitations in linker chemistry. Here we systematically explore the energetic and structural effects of rigid and flexible linkers on the binding of a fragment-based inhibitor of human uracil DNA glycosylase. Analysis of the free energies of binding in combination with cocrystal structures shows that the flexibility and strain of a given linker can have a substantial impact on binding affinity even when the binding fragments are optimally positioned. Such effects are not apparent from inspection of structures and underscore the importance of linker optimization in fragment-based drug discovery efforts.
- Research Organization:
- Brookhaven National Laboratory (BNL) National Synchrotron Light Source
- Sponsoring Organization:
- DOE - OFFICE OF SCIENCE
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 1020117
- Report Number(s):
- BNL--95966-2011-JA
- Journal Information:
- Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 6 Vol. 5; ISSN 1552-4450
- Country of Publication:
- United States
- Language:
- English
Similar Records
Mimicking Damaged DNA with a Small Moleclue Inhibitor of Human UNG2
Influence of Linker Structure on the Anion Binding Affinity of Biscyclopeptides