Computational Drug Discovery and Design

PI3Kδstructure by going toFile!Fetch by ID. In the newly

opened window, selectPDB, type4XE0 in the adjacent blank

form, and press theFetchbutton, which will load the PI3Kδstruc-

ture. By pressing the left button of the mouse and moving the

cursor over the window, we can rotate the protein, observe its

secondary and tertiary structures, and examine the binding mode

of idelalisib (40L). Next, use the ligand coordinates to delimitate

the target binding site for the molecular docking simulations (see

Note 3). To do this, go toSelect!Residue!40L, and zoom in to

it by selectingActions!Focus. This step will generate the image

shown in Fig.1b. Using the mouse to rotate the structure, identify

the sole asymmetrical carbon of idelalisib. Select this atom by

pressing Ctrl and the left mouse button. Find its coordinates by

going toFavorites!Command Lineand typing the following line

in the newCommandfield at the bottom of the Chimera interface:

getcrd selection

This action will generate a new line in the status bar (lower area

of the window). The status bar contains the description of the

selected atom followed by its X, Y, Z Cartesian coordinates. Record

these numbers in a footnote; they will be used to define the center

of the binding site. If selecting the asymmetrical carbon atom is

difficult, replaceselectionin the above command by::40L@C19to

obtain the same result. Finally, remove the crystallographic ligand

from the binding site by going toSelect!Residue!40Land

Actions!Atoms/Bonds!delete.

The binding site of PI3Kδdoes not contain unusual residue

types or electronic states; however, these odd configurations can

occur in some crystallographic structures. It is advisable to always

verify the presence of uncommon representations and fix them

whenever required. This verification can be performed using the

Fig. 1(a) Molecular structure of idelalisib. (b) View of the PI3Kδenzyme (PDB ID:4XE0)—idelalisib complex.
The protein backbone is in cartoon representation. The ligand and residues in the binding site are depicted as
sticks. Water molecules are illustrated as spheres

40 Ricardo N. dos Santos et al.