Ligand deconstruction: Why some fragment binding positions are conserved and others are not.

ABSTRACT: Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even whe

SUBMITTER: Kozakov D 

PROVIDER: S-EPMC4443342 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature