## 3 Results and Discussion
### Molecular Docking
#### 3.3.3 Phosphatidylinositol 4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma Isoform  
The phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, also known as PI3K-C2\(\alpha\), belongs to the family of phosphoinositide 3-lipid kinases, which consists of eight distinct PI3-kinase catalytic subunits [62]. In humans, these eight isoforms have been categorized into three functional classes [63] based on their protein domain structure, lipid substrate specificity, and associated regulatory subunits. The class I enzymes include p110\(\alpha\), p1108, p1108, and p110\(\gamma\). The class II enzymes consist of PI3K-C2\(\alpha\), PI3K-C2\(\beta\), and PI3K-C2\(\gamma\). Lastly, the class III enzyme is known as Vps34. PI3K, known for its capability to phosphorylate the hydroxyl group at the 3 position of phosphatidylinositol lipids [62], plays a crucial role in transducing signals from various growth factors and cytokines. This transduction process involves the generation of phospholipids that activate the serine/threonine kinase AKT and other downstream effector pathways [64]. Extensive research has highlighted the involvement of PI3K in diverse cellular processes such as cell growth, survival, differentiation, motility, proliferation, and intracellular trafficking [63]. Consequently, inhibitors targeting these enzymes are considered potential therapeutic targets for cancer treatment. As a transferase enzyme, it plays a crucial role in facilitating the phosphorylation of 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) using ATP. This enzymatic process leads to the generation of ADP and 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate). Its crystal structure contains one single chain named A and was found complexed with 0 TA ligand or (2-Amino-8-Cyclopentyl-4-Methyl-6-(1h-Pyrazol-4-Yl) pyrido [2,3-D]pyrimidin-7(8h). The docking validation shows that OTA was bound in the active site with mostly hydrophobic interactions with several residues, including Met953, Met804, Phe961, Ile963, Ile831, Ile879, Ile881, Val882, and Tyr867. In addition to a Pi-sulfur interaction with Met953. OTA establishes a crucial carbon-hydrogen bond with Lys833 and two conventional hydrogen bonds with Val882 through its aminopyrimidine function. These interactions were deemed critical for the inhibition mechanism [65]. Mol1 and Mol2 exhibit moderate PLPchem scores and are ranked lower compared to other compounds targeting PI3K-C2\(\alpha\), indicating their moderate stability. Notably, both Mol1 and Mol2 share the same mode of action toward this target, forming crucial interactions with key residues involved in phosphorylation. They both establish hydrogen  
Figure 2: The 3D structure shows the most favorable Ca3 complexes after docking, with the inhibitors (Mol3 and Mol5) displayed in stick form and colored using default atom colors. bonds with Val882 and engage in multiple hydrophobic interactions, including alkyl and Pi-alkyl interactions with Ile963, Met804, Pro810, and Ile831. Additionally, a Pi-sulfur interaction was observed with Met953 for both compounds. These findings suggest that Mol1 and Mol2 can serve as a model for PI3K-C2\(\alpha\) and confirm their strong affinity to it. Mol3, Mol4, and Mol5 displayed nearly identical PLPChem scores (Table 5). Among them, Mol3 performed the best with a slight advantage over Mol5 (Figure 3), despite their significant difference in molecular weight. Mol5, on the other hand, ranked second among all compounds and demonstrated high stability in two targets, FAK and Ca3. Both Mol3 and Mol5 were found to be closely integrated within the binding site, adopting the same mode of action toward PI3K-C2\(\alpha\) and forming crucial interactions with key phosphorylation-involved residues. They established two carbon-hydrogen bonds, one with Ser806 and the other with Ile881, indicative of high stability. Additionally, they engaged in multiple hydrophobic interactions, including alkyl and Pi-alkyl interactions with Ile963, Ile879, Pro810, and Ile831.