medical dating site - Accommodating protein flexibility for structure based drug design

Conversely, ligand binding leads to substantial conformational changes in therapeutic targets such as aldose reductase (17), dihydrofolate reductase (2), and t RNA-guanine transglycosylase (18), but here the perturbations among the ligands have often not been systematic enough to disentangle changes in ligand size and polarity, making it harder to isolate the receptor conformational changes involved and their origins.In addition, similar ligands can adopt dissimilar binding modes in the same protein (19).Ideally, one would like series of ligands where size and physical properties are increased incrementally without introducing other perturbations that could change binding determinants.

accommodating protein flexibility for structure based drug design-5

Here we investigate eight congeneric ligands that grow by single-methylene additions, determining their protein-bound structures by X-ray crystallography, to investigate how a protein accommodates these changes.

Rather than changing conformation smoothly to complement the ever-larger ligands, the protein site adopts a few discrete conformations as it expands.

The importance of conformational flexibility in protein–ligand interactions is widely acknowledged.

Structural studies of model systems such as dihydrofolate reductase (1, 2), cyclophilin A (3), adenylate kinase (4), and others (5, 6) have suggested that conformational changes in the protein are coupled to progress along the catalytic reaction coordinate, and that local fluctuations can affect coupling between binding and global transitions (7).

Using multiconformational crystallographic refinement, we investigated whether the new conformations of the cavity were accessible to the ground state or were more distant in energy.

Expecting continuous changes among conformations, we were surprised by the structures that emerged.

Because only benzene may be readily accommodated by the apo cavity but most other members of the series bound with greater affinity, this series seemed well-suited to exploring ligand-provoked conformational changes.

We asked whether the cavity continuously adapted its conformation to these incremental enlargements in ligand size or whether instead the cavity jumped to discrete conformational states.

Inspection of the few other homologous series in the Protein Data Bank suggests that such discrete conformational adaptations to ligand binding are common, and may be an important consideration in ligand design.

Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention.

Many medicinal chemistry programs change ligands incrementally to explore protein binding and to optimize binding affinity.

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