Page 129 - ITPS-7-2

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

characterized by bond distances between certain atoms the pyridine ring of T85 at a distance of 5.30 Å and an angle
of T85 and side chains of the target, including VAL 850, of 88.8º. Both π-π stacking interactions were coordinated
VAL 851, and LYS 802. The architecture of the hydrogen in T-shaped configurations within the binding site of the
bond interactions includes the H-N•••H between T85 and 6PYS protein complex. This type of configuration involves
VAL 851 residue at a bond distance of 2.12 Å; the C-O•••H quadrupole interactions among delocalized electrons
between VAL 851 residue and T85 at a bond distance of in π-orbitals, leading to enhanced intermolecular
1.88 Å; and the N-H•••O between amino acid residue LYS electrostatic interactions. 97,98 Therefore, having multiple
802 and T85 at a bond distance of 2.05 Å. The architecture π-π stacking interactions between aromatic compounds
suggests that the hydrogen bonds formed within the between T85 and 6PYS suggested increased binding
computed bond distances indicate strong hydrogen bonds affinity and specificity of the ligand-protein interaction,
necessary for the effective binding of T85. which provided additional stabilizing forces and shape

Figure 14 also presents another type of non-covalent complementarity.
interaction in our simulation, revealed as π-π stacking 3.6.3. ADMET Investigations
interactions. The distance and angle of the intermolecular
contribution of π-π stacking interaction between the To investigate the metabolic stability and safety profiles of
planes of the fluorine-associated oxazole aromatic ring T85, we assessed its clinical relevance using the QikProp
of T85 and the indole ring of TRP 780 side-chain was program in Schrödinger Maestro. For this, we utilized all
computed at 5.42 Å and 89.7º. More so, another π-π generated descriptors by QikProp, relevant for ADMET
stacking interaction existed at a different space within predictions to evaluate the pharmacokinetic profiles of
99
the binding site. This interaction manifested between the T85. Table 5 displays a host of descriptors computed by
hydroxyphenyl ring along the side-chain of TYR 836 and QikProp with their optimal tolerance ranges following
Table 5. Evaluation of the pharmacokinetic attributes of T85 ligand from Schrödinger’s ADMET descriptors 99

Descriptors Description Range or T85
recommended
values
#stars The quantity of attribute or descriptor values for known medications that are 0 – 5 0
outside the 95% range of comparable values. A molecule with more stars than
a few indicates that it is less drug-like than the other molecule. The quantity,
#rotor, donorHB, accptHB, glob, QPpolrz, PlogPC16, QPlogPoct, QPlogPw,
QPlogPo/w, logS, QPLogKhsa, QPlogBB, #metabol, and the following
attributes and descriptors are taken into account while determining the #stars.
#amine Quantity of amine groups that are not conjugated. 0 – 1 0
#amidine Quantity of amidine and guanidine groups. 0 0
#acid Count of groups of carboxylic acid. 0 – 1 0
#amide Count of non-conjugated amide groups. 0 – 1 0
#rotor Number of rotatable bonds that are non-trivial (not CX3) and non-hindered 0 – 15 7
(not amide, tiny ring, or alkene).
#rtvFG Reactive functional group count. These groups have the potential to cause 0 – 2 0
toxicity, decomposition, or reactivity issues in vivo, as well as false-positive
results in HTS assays.
CNS CNS is measured on a scale ranging from -2 (indicating no activity) to+2 −2 (inactive), +2 -2
(indicating full activation). (active)
Mol_MW (in Daltons, Da) The molecule’s molecular weight. 130.0 – 725.0 435.429
dipole† The molecule’s calculated dipole moment. 1.0 – 12.5 10.969
SASA SASA (total solvent accessible surface area), measured in square angstroms 300.0 – 1000.0 648.546
with a 1.4 Å radius probe.
FOSA The SASA’s hydrophobic component (saturated carbon and attached hydrogen). 0.0 – 750.0 208.350
FISA The SASA’s hydrophilic component (SASA on N, O, H on heteroatoms, and 7.0 – 330.0 205.152
carbonyl C).
(Cont’d..)

Volume 7 Issue 2 (2024) 19 doi: 10.36922/itps.2340