Page 121 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences PI3K-α inhibitors for cancer immunotherapy

enclosure score and the druggability score, indicating that indicating a strong and favorable interaction of the ligand
a rise in the druggability score corresponds to a higher with the target receptor, suggesting a higher potential for
degree of cavity enclosure, represented by the enclosure binding and therapeutic activity of optimal efficacy.
score. A higher enclosure score suggests an envelope Figures 5-9 depict the computed results for the
with a tighter barrier that would prevent ligands from binding site exposure score, which explains the degree of
releasing once it is enclosed. Hence, an enclosure score accessibility or availability of the binding site to interact
of 0.8035 depicted a high-affinity enclosure (potentially with a ligand, as well as its openness to solvents. However,
stimulus-sensitive) for the 6PYS human PI3K-α protein to in Figures 5-9, the exposure scores of the SiteMaps range
envelope a ligand and act as a diffusion barrier, providing from 0.5405 – 0.6446. A lower exposure score indicates
an excellent slow release. 56 a deeper or well-encapsulated site favorable for excellent
Conversely, the pocket hydrophilicity (hydrophilic ligand-protein binding. More so, for a favorable binding,
interaction score) of the protein depicted an inverse the Van der Waals contact with the receptor should lie
correlation with the druggability score, as illustrated in at least 4 Å from the nearest protein atom. Hence, the
Figures 5-9. The hydrophilicity of the binding pockets numeric value of the exposure score of SiteMap 5 (Figure 9)
primarily favors polar ligands, which have a strong suggested that better molecular mechanotransduction
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affinity for water and are soluble in water. Although the could occur, due to a deeper and better-encapsulated site
results shown in Figures 5-9 are approximately identical, location in the receptor for ligand binding. 55
SiteMap 5 obtained the best hydrophilic interaction score The dynamics around the hydrophobicity of a binding site
of 1.1301, indicating that the binding site provided a is another important property that ensures the presence of
better hydrophilic environment with a higher affinity for hydrophobic characters necessary for high binding affinity.
interacting with polar ligands and water compared to other Hydrophobicity is a characteristic that measures the extent
binding sites. to which a molecule is able to repel water. Proteins tend
In addition, Figures 5-9 present the computed results of to bury hydrophobic residues within their core during the
the volume of potential binding sites from the respective folding process to stabilize the protein structure and prevent
SiteMaps. The volume of the binding pocket plays a aggregation. However, the hydrophobic interaction score
significant role in the process of rational drug discovery. The measures how effectively hydrophobic molecules interact
size and shape of the drug molecule that can successfully with each other in a solvent environment. Figures 5-9
bind to the protein depend on the volume of the binding depict the results of the respective SiteMaps’ hydrophobic
pocket. While a smaller binding pocket might be better interaction scores. The hydrophobic interaction score for
suited for tiny molecules, a larger binding pocket might SiteMap 4 (Figure 8) was 0.7735, ranking top among all
be able to accommodate larger medication molecules. In the SiteMaps assessed. This result depicted a region with a
Figures 5-9, binding SiteMap 1 suggested a larger binding higher propensity for stronger hydrophobic binding sites
volume of 2067.6040 Å when compared to the other to bind to ligands with higher affinity. In general, entropic
3
binding SiteMaps. In any case, a well-fitted ligand into the phenomena cause hydrophobic molecules to interact with
receptor pocket can trigger signaling transduction, while a each other in water. 57
mismatch in volume fitting may decrease responses.
3.4. Molecular docking analyses
Figures 5-9 display the result of the ligand-receptor
complex contact score. The contact score is a property that In this study, we report a comprehensive workflow involving
evaluates the strength of the average site-point interactions, three stages of virtual screening processes: HTVS, SP, and
such as hydrogen bonding, electrostatic interactions, XP modes that simultaneously incorporated molecular
hydrophobic interactions, and non-bonded Van der docking at each stage to discover potential top-performing
Waals interactions with the receptor. These interactions PI3K-α inhibitors for the suppression of human PI3K-α-
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contribute to the stability and strength of the ligand- related problems.
receptor complex and are essential for effective binding. Table 1 reveals four potential candidates identified
The contact score provides a numerical value representing as top-ranked inhibitory molecules from the virtual
the quality of the ligand-receptor interaction, calibrated screening and docking of several ligands on the human
such that the average score for the sub-micromolar sites 6PYS protein complex. The molecular docking results of
is 1.0, facilitating comparison between sites, where a these compounds revealed that the structural motifs of
higher value indicates better interaction. In Figures 5-9, the top-ranked potential inhibitory molecules that could
the contact score ranged from 0.8492 – 1.0307. SiteMap bind to the 6PYS human PI3K-α protein consisted of
5 possessed the highest contact score value (1.0307), cyclic sulfonamide derivatives attached to pyridine cores,

Volume 7 Issue 2 (2024) 11 doi: 10.36922/itps.2340