OptiDock: virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space.
Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library. These compounds are docked individually using the FlexX program (Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. J. Mol. Biol. 1995, 251, 470-489) to define distinct docking modes in terms of reference placements for combinatorial core atoms. Thereafter, substituents in R-cores (consisting of the core structure substituted at a single variation site) are docked, keeping the core atoms fixed at the coordinates dictated by each reference placement. Interaction energies are calculated for each docked R-core with respect to the target protein, and energies for whole compounds are calculated by finding the reference core placement for which the sum of corresponding R-core energies is most negative. The use of diverse whole compounds to define binding modes is a key advantage of the protocol over other combinatorial docking programs. As a result, OptiDock returns better-scoring conformers than does serially applied FlexX. OptiDock is also better able to find a viable docked pose for each library member than are other combinatorial approaches.
Sprous
Dennis G
DG
Tripos Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA.
Lowis
David R
DR
Leonard
Joseph M
JM
Heritage
Trevor
T
Burkett
Steven N
SN
Baker
David S
DS
Clark
Robert D
RD
D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000295:instrumentation* / Q000379:methods*; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D012984:Software; D013816:Thermodynamics
D008024:Ligands; D011506:Proteins