 |
|
Title
|
|
Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery.
|
|
|
Authors
|
|
M.Fischer,
R.G.Coleman,
J.S.Fraser,
B.K.Shoichet.
|
|
|
Ref.
|
|
Nat Chem, 2014,
6,
575-583.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Proteins fluctuate between alternative conformations, which presents a challenge
for ligand discovery because such flexibility is difficult to treat
computationally owing to problems with conformational sampling and energy
weighting. Here we describe a flexible docking method that samples and weights
protein conformations using experimentally derived conformations as a guide. The
crystallographically refined occupancies of these conformations, which are
observable in an apo receptor structure, define energy penalties for docking. In
a large prospective library screen, we identified new ligands that target
specific receptor conformations of a cavity in cytochrome c peroxidase, and we
confirm both ligand pose and associated receptor conformation predictions by
crystallography. The inclusion of receptor flexibility led to ligands with new
chemotypes and physical properties. By exploiting experimental measures of loop
and side-chain flexibility, this method can be extended to the discovery of new
ligands for hundreds of targets in the Protein Data Bank for which similar
experimental information is available.
|
|
|
|