 | Putative
Ligand Virtual Screening and Lead Generation - Once putative binding sites
have been determined on the target proteins, the next stage is to look for ligands
that can modulate the activities of these proteins. This is done with virtual
screening methods, specifically docking ligands into these binding sites and estimating
how strongly they bind. Here the Center is focusing on the FlexX and FlexE programs
of Tripos which perform flexible docking calculations. These programs use a rapidly
evaluated scoring function to estimate the relative binding affinities of ligands
which includes some components from standard molecular mechanics force fields
but also has additional statistics-based potentials to include, for example, solvent
effects without explicitly including solvent. These current programs include the
ability of the ligand to change its conformation, which is a very important feature
to include for the scorings to reflect reality. Further, FlexE includes flexibility
of the protein which is also important to include but has been ignored because
of the difficulty of including this feature. This is done by using molecular dynamics
to create an ensemble of protein conformations. Each of these conformations is
then docked using the normal flexible ligand program but then the overall score
is based on a combination of these individual scores over the whole ensemble.
The initial leads for ligands can be found by using the above procedures to screen
libraries of known small molecules for putative binding or by de novo ligand generation
procedures which, given an active site definition, create novel molecules which
may interact with it. One example of a program that does de novo ligand generation
is SPROUT. |
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