Page 131 - ITPS-7-2

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

Table 5. (Continued)
Descriptors Description Range or T85
recommended
values
PercentHumanOralAbsorption On a 0 – 100% scale, the predicted oral absorption by humans. An analysis >80% is high, <25% 70.217
of multiple linear regression data provides the basis for the forecast. is poor
HumanOralAbsorption and this attribute measure the same thing, hence
their correlation is typically good.
SAFluorine The solvent-accessible surface area of fluorine atoms. 0.0 – 100.0 51.967
SAamideO The solvent-accessible surface area of amide oxygen atoms. 0.0 – 35.0 0
PSA Van der Waals surface area of polar nitrogen and oxygen atoms and carbonyl 7.0 – 200.0 141.097
carbon atoms.
#NandO Number of nitrogen and oxygen atoms. 2 – 15 10
RuleOfFive Number of violations of Lipinski’s rule of five. The rules are: mol_MW<500, Maximum is 4 0
QPlogPo/w < 5, donorHB ≤ 5, accptHB ≤ 10. Compounds that satisfy these
rules are considered drug like. (The “five” refers to the limits, which are
multiples of 5.).
RuleOfThree Number of violations of Jorgensen’s rule of three. The three rules are QPlogS Maximum is 3 0
> -5.7, QP PCaco>22 nm/s, # Primary Metabolites<7. Compounds with
fewer (and preferably no) violations of these rules are more likely to be
orally available.
#ringatoms Number of atoms in a ring. 21
#in34 Number of atoms in 3- or 4-membered rings. 4
#in56 Number of atoms in 5- or 6-membered rings. 17
#noncon Number of ring atoms not able to form conjugated aromatic systems (e.g., sp C). 3
3
#nonHatm Number of heavy atoms (non-hydrogen atoms). 30
Jm Predicted maximum transdermal transport rate, Kp×MW×S (μg cm hr ). 0.01
−1
−2
The parameters (K and S) are obtained from the aqueous solubility and skin
p
permeability, QPlog K and QPlogS.
p
95% of known drugs gleaned from a retrospective specific lipids in the cell membrane, thereby activating
evaluation of drugs by the World Drug Index (WDI) to downstream signaling pathways. It is connected to the
serve as a baseline for molecules. The drug-likeness and frequently dysregulated PI3K/AKT/mTOR pathway in
pharmacokinetic attributes of a compound are important cancer. Increased signaling through this route can result
considerations in drug development to guarantee that the from abnormal activation or mutations in PI3K-α, which
molecule exhibits favorable characteristics for absorption, supports cell survival, proliferation, and resistance to
distribution, metabolism, excretion, and toxicity properties cell death. Such an imbalance may contribute to the
while possessing appropriate physicochemical properties development and spread of cancer. Mutations in the
for potential therapeutic use. Interestingly, T85 complied PIK3CA gene, which codes for the PI3K-α catalytic
with the ADMET descriptors put forward by QikProp, and subunit, are frequently observed in cancer types such as
results were within optimal tolerance bounds, especially lung, ovarian, colorectal, and breast cancers, contributing
Lipinski’s rule of five, Jorgensen’s rule of three, the blood/ to increased PI3K activity and abnormal signaling that
brain barrier (BBB) penetration, access to the central promotes cancer. To effectively target PI3K-α and other
nervous system, dermal penetration parameter (QPlogK ), members of the PI3K/AKT/mTOR pathway, it is critical
p
blockage of human ether-a-go-go-related gene potassium to rationally design potent multitarget inhibitors to
ion (hERG K ), and so on, even the Verber rule. The address the heterogeneity and complexity of cancer cells,
+
100
result culminated in the suitability of T85’s development as as well as the emergence of drug resistance and toxicity.
a promising inhibitor for PI3K-α. In this study, we obtained the human PI3K-α protein
(6PYS) co-crystallized with a ligand (PJ5) and selected
4. Conclusion PI3K-α inhibitors from protein and binding databases,
The enzyme PI3K-α plays a crucial role in regulating the respectively. The dataset comprised a congeneric series of
growth, division, and survival of cells by phosphorylating 3D structures of selected PI3K-α inhibitors, which were

Volume 7 Issue 2 (2024) 21 doi: 10.36922/itps.2340