Computational Drug Discovery and Design

3.3 Configure,
Perform, and Analyze
the Molecular Docking
Experiment
with the FlexAID
Interface

The FlexAID interface permits users to adjust the parameters of

FlexAID in a convenient environment. The basic view of the inter-

face contains four tabs:Input Files,Target Config,Ligand Config,

andSimulate. The functionalities of each tab are reviewed in detail

in the following sections. The FlexAID interface contains three

menu items in the top left hand corner:LoadandSavesessions

(seeNote 21), andShow,which turns on the display of two addi-

tional tabs:Scoring Cfg(scoring function configuration) andGA

Params(genetic algorithm parameters).These tabs are needed for

theoptionalsections of the following protocol.

1. Open the FlexAID interface from the Plugin menu found in
   the main window of PyMOL.

Plugin!NRGsuite!Open FlexAID...

2. TheInputtab is displayed by default upon FlexAID’s opening
   and allows configuration of the target and ligand (seeNote 22).
   First, select “3b7e” from the PyMOL objects/selection drop-
   down menu and click “Save as target” (seeNote 20). Then,
   select “ZMR” from the drop-down menu and click “Save as
   ligand” (seeNote 20).


3. Click on theTarget Cfg(target configuration) tab in the Flex-
   AID interface window to access the parameters of the target (see
   Note 23). After selecting a target and a ligand, the definition of
   the binding site is the third mandatory input to perform a
   simulation. In the “Binding-site definition” upper box, under
   “Choose binding-site type,” click on “CLEFT” and then click
   on the button “Import clefts.” Select the first cleft which
   should be named “3b7e_sph_1” (seeNote 24). A new object
   named “BINDINGSITE_AREA__” will be created in the
   PyMOL viewer and the red cleft will appear with the mesh, a
   grid like, representation.

(Optional) Although there is no need to consider target flexi-

bility for the docking of zanamivir into the neuraminidase, it is

crucial to keep in mind that the docking of any ligand that has

not been crystallized with the target might benefit from the defin-

ing of key residues on the target in the binding site that interacts

with the ligand as flexible. Even when flexibility is not critically

needed to retrieve the binding mode of reference, the accuracy of

the simulation may improve when highly mobile side chains can

change conformations (seeNote 25). There are two options to

include flexibility in the target in the “Side-chain flexibility” section

of the “Target flexibility” box: (1) the “Add/Delete flexible side-

chains” wizard button, which allows the interactive selection of

specific side-chains by the user in the PyMOL viewer, and (2) the

“Residue code” text entry form, which quickly activates the flexi-

bility for a given residue of the target. In our current case, the key

Molecular Docking in Computational Drug Discovery and Design 375