Computational Drug Discovery and Design

high-resolution X-ray structure. Nevertheless, this crystallographic

model is able to provide good molecular docking results as will be

demonstrated in the next sections [46, 47].

3.2 Single-Ligand
Docking

3.2.1 Generating
the Ligand

Now that we have an overall view of the system to be studied, we

can generate the input files to perform the molecular docking

analysis. First, open a text terminal (also known as the console) in

your OS, and use the following commands to generate a working

folder namedDocking:

mkdir Docking

Next, move to this folder by typing:

cd Docking

Then generate a new 3D structure of the ligand idelalisib

(distinct from the crystallographic one) to use an equitable input

conformation for the docking analysis. Instead of directly drawing

the 3D structure of the ligand using a molecular editor, a safer

protocol is to sketch a 2D structure and then use this file to

automatically generate the 3D representation. This approach is

useful for handling compounds with large or intricate structures

that contain charged groups and asymmetric carbons, such as those

commonly found in natural products. In these cases, drawing 3D

structures from scratch can become a significant source of error.

Looking at the structure of idelalisib (Fig.1a), we can use BKChem

to reproduce it in a 2D format. Open BKChem by typingbkchemon

the terminal. After drawing the full structure (with the correct

chirality), the generated data should be saved inmolextension by

selectingFile!Export!Molfileand should be namedligand.mol

in theDockingdirectory. Finally, type the following command to

convert the idelalisib 2D structure into apdb 3D model with

optimized geometry using Open Babel:

obabel -imol ligand.mol -h -opdb -O ligand.pdb --gen3d

–minimize

The generated 3D structure of the compound will be observed

in the UCSF Chimera environment. To do this, open chimera

through the installation icon, go toFile!Open, and select the

fileligand.pdb.Another way to open the file in Chimera is to type

the following in the terminal:

chimera ligand.pdb

3.2.2 Generating
the Receptor

Now, we will use the crystallographic structure of PI3Kδto gener-

ate the input file for the receptor. In the Chimera interface, load the

Molecular Docking and Structure-Based Virtual Screening 39