growth. These kinases catalyze the conversion of phosphatidylino-
sitol 4,5-bisphosphate (PIP 2 ) to phosphatidylinositol 3,4,5-
trisphosphate (PIP 3 ), which activates downstream intracellular sig-
naling cascades. PI3Kδbelongs to class I PI3Ks and is predomi-
nantly expressed in leukocytes; therefore, it represents a potential
target for the treatment of hematological diseases.
Idelalisib (Zydelig®, Gilead Sciences) is an inhibitor of PI3Kδ
that was recently approved by the FDA for the treatment of chronic
lymphocytic leukemia and indolent non-Hodgkin’s lymphomas
[41–44]. This chapter uses the idelalisib-PI3Kδcomplex to run
the molecular docking protocol (seeNote 3). First, we will predict
the binding mode of idelalisib to PI3Kδ. Next, we will use the same
system to run an SBVS against a large compound database. This
part of the chapter is intended to familiarize the reader with ele-
mentary tasks concerning chemical library acquisition, SBVS run-
ning, and analysis of results.3.1 Characterization
of the Macromolecular
Target
The X-ray structure of the PI3Kδ-idelalisib complex can be down-
loaded by entering the code4XE0in the search box of the PDB
interface (http://www.rcsb.org/)(seeNote 3). Each PDB entry
contains information on experimental details, related literature, the
biological relevance of the macromolecule, and statistical indicators
on the quality of the 3D model. Accordingly, on the first page of the
4XE0entry, the Structure Summary tab (Macromolecules section)
shows that this macromolecular structure is formed by a polypep-
tide chain composed of 939 amino acid residues. The Small Mole-
cules section provides information about the presence of
low-molecular weight compounds as elements of the crystallo-
graphic complex. In this section, idelalisib is identified by its struc-
ture and IUPAC name. This inhibitor is distinguished within the
crystallographic structure by the code40L.
Important points that should be noted when selecting a 3D
molecular model are the statistical parameters that indicate the
quality of the structure. Despite the existence of many other indi-
cators, the resolution of the X-ray structure is the key parameter
that measures the overall quality of the model. In a simple defini-
tion, the crystallographic resolution expresses how well detailed the
electron density map is that was used to specify the coordinates of
each atom in the 3D structure. Lower values mean a higher resolu-
tion and, consequently, higher accuracy in the assignment of the
atom coordinates. While structures with resolution under 1.5 A ̊are
particularly suited for molecular docking, lower-resolution models
(~3 A ̊) can be used as long as we keep in mind that uncertainty in
atom coordinates always increases with the value of the
resolution [45].
Returning to the Structure Summary tab and looking at the
Experimental Data and Validation section, we observe that
although 4XE0 has the acceptable value 2.43 A ̊, it is not a38 Ricardo N. dos Santos et al.