eHiTS: Electronic High Throughput Screening
Author: Zsolt Zsoldos
Affiliation: SimBioSys Inc., 135 Queen's Plate Drive, Unit 355, Toronto, ON, M9W 6V1 Canada
Abstract:
Published flexible docking algorithms aim to predict
exact binding positions and orientations, a very demanding task, which
makes the resulting software too slow for screening large compound libraries.
Furthermore, most of these methods employ built in, hard coded scoring
systems for filtering the hits based on a very specific chemistry model.
Such limitation is undesireable in light of the fact, that receptor-ligand
interaction scoring is still subject to heated debates in the scientific
community.
This poster presents a novel method, which is
capable of extremely fast flexible pre-docking of a large set of
candidate ligand structures into a target cavity. The cavity description
consists of a steric shape grid and a user selectable set of chemical
properties. The later set may include hydrogen bond donor and acceptor
potentials, hydrophobicity, electrostatic potential and other more
specific interaction types, e.g. Pi-Pi interaction or metal ion interactions.
Both hydrogen bonding and electrostatic potential interactions are
handled with two independent field descriptors (donor and acceptor separately,
positive and negative charge probe also separately) providing parallel
representation possibility of variable protonation states and tautomerism.
Both steric and chemical descriptors can be automatically generated by
the system from a receptor structure presented as a PDB file input. Alternatively,
the target cavity description can be based on a pharmacophore model or
a CoMFA study of overlayed lead compounds.
Another very important feature of the eHiTS system
is its exhaustive nature. A systematic algorithm is used in eHiTS with
no random, stochastic or evolutionary element. Therefore, eHiTS provides
comprehensive search space coverage unlike other methods, which are limited
to finding an arbitrary subset of possible solutions due to their use of
sampling. The eHiTS system generates all major docking modes, that are
compatible with the steric and chemistry constraints of the target cavity
for each candidate structure. The output consists of multiple sets of 3D
coordinates per structure with rough fitness scores, that are highly configurable.
The solutions could be used as starting points for more involved energy
minimisation studies (finding local minimum around the proposed position)
to predict more exact binding modes and affinities.
Some preliminary test results are presented detailing
the application of the system to screening studies of HIV, Thrombin and
COX2 inhibitors using candidate datasets from 3D databases.
For more information, see the company's web site:
http://www.simbiosys.com/ |
