The search for strongly binding ligands to a specific
receptor can be a very tedious task. High throughput screening (HTS)
is typically used to screen huge libraries of compounds for activity. However,
HTS is costly and time consuming considering the size of these libraries
are on the order of millions of compounds. In recent years, virtual
high throughput screening methods (VHTS) have been used to economize the
time and cost of searching for active complexes. Most of the VHTS methods
utilize simple statistical filters, e.g. fingerprints describing the
existence of certain functional groups (2D substructures), or matching
of simple rule systems like the Lipinsky rules. Those methods are fast but
crude. They do not take into account the complex shape and 3D structure of
the protein binding site and the ligand, which is proven to be key factor
in the binding of ligands.
As an alternative, there are numerous flexible
ligand docking tools, that consider 3D shape fitting as well as chemical
complementarity between ligand and receptor. However, most of the docking
tools are either too slow for screening large libraries or are not accurate enough.
The eHiTS (electronic High Throughput Screening) software
provides a unique solution to this problem by performing accurate
flexible ligand docking at speed approaching the crude VHTS methods.
The flexible ligand docking problem
is often divided into two subproblems: pose/conformation search
and scoring function. For virtual screening the search algorithm should
have the following desired properties: fast, provide a manageable
number of candidates and able to find the optimal pose/conformation of
the complex. Algorithms employing stochastic elements or crude
rotomer samplings fail to satisfy the last criterion.
The software offers new approaches to both subproblems.
A 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.