Accommodating protein flexibility for structure based drug design

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Durrant, Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093, 858-822-0169 (Office), 858-534-4974 (Fax), [email protected] Protein flexibility plays a critical role in ligand binding to both orthosteric and allosteric sites.We here review some of the computer-aided drug-design techniques currently used to account for protein flexibility, ranging from methods that probe local receptor flexibility in the region of the protein immediately adjacent to the binding site, to those that account for general flexibility in all protein regions.The induced-fit and population-shift theories of ligand binding are not mutually exclusive.To varying degrees, it is likely that both effects contribute to ligand binding [11].Medicinal chemists engaged in computer-aided drug design (CADD) must account for this flexibility if they wish to successfully identify small-molecule ligands .Traditionally, a single static protein structure has been used in CADD projects.

Future studies may identify novel antichagastic therapeutics that exploit this cryptic pocket as well [18].

We here review some of the CADD techniques currently used to account for protein receptor flexibility, ranging from methods that probe local receptor flexibility in the region of the protein immediately adjacent to the binding site, to those that account for general flexibility in all protein regions.

A number of methods have been developed that account for the flexibility of those residues immediately adjacent to the ligand-binding site.

A ligand in solution encounters a highly dynamic protein that fluctuates between multiple, low-energy states.

After initial binding, the ligand stabilizes a certain subpopulation of those states.

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