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KALAYCI ET AL.
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tetrahydroisoquinolynyl‐benzoic acid compounds (4a–g and 6a–g)
have been reported to be in the permissible value range. Volume
(774.46–1315.30), which is the total solvent‐accessible volume
descriptor, was determined to be in the permissible range for
these target analogs (4a–g and 6a–g), compared with reference
values. The logP values, such as QPlogPoct, QPlogPw, QPlogPo/w,
QPlogS, QPlogHERG, QPlogBB, QPlogKp, and QPlogKhs, range
from 13.80 to 23.51, 9.87 to 16.08, 12.76 to 16.08, −5.29 to −2.19,
−4.29 to −2.30, −2.82 to −1.37, −6.61 to −3.91, and −0.76 to −0.21,
respectively, indicating that these analogs (4a–g and 6a–g) have a
high capacity. The values of human oral absorption (HOA) range
between 36.03% and 72.26%, and the van der Waals surface area
of polar nitrogen and oxygen atoms (PSA) is in the range of
114.32–194.14, indicating that all derivatives (4a–g and 6a–g) had
the acceptable values. All the analogs (4a–g and 6a–g) have dis-
played poor Caco‐2 cell permeability values (except for com-
pounds 4a, 4e, 4g, and 6f; QPPCaco, 2.25–53.45) and
Madin–Darby canine kidney (MDCK) cell permeability values
(except for compound 6f; QPPMDCK, 0.87–26.54). Indeed,
all newly synthesized methylene‐aminobenzoic acid and
tetrahydroisoquinolynyl‐benzoic acid derivatives (4a–g and 6a–g)
displayed good drug‐like properties with zero violation of
Lipinski's rule, one violation of the Jorgensen's rule (except for
compounds 4a–b, 4e, 4g, and 6f), and zero pan‐assay interference
compounds (PAINS) alerts (except for compounds 4b–d and
4f; Table 3). Moreover, the ADME–Tox values calculated for 2,
2‐dimethyl‐1,3‐dioxan‐4‐one‐substituted compound 6f might ex-
plain why, being a potent AChE inhibitor, this ligand has the most
AChE inhibitory activity in biological experiments (Figure S1).
compared with reference compounds derived from the corre-
sponding 6I0L, 4E3D, and 5HF9, and the docking poses were su-
perimposed. As expected, RMSD scores were computed as <2 Å,
that is, 1.11, 0.17, and 0.95 Å, respectively.
In the present in silico docking study, the docking pattern of
HI6 was compared with analog 6f (KI of 13.62 0.21 nM for
AChE), which is the most active derivative of the new methylene‐
aminobenzoic acid and tetrahydroisoquinolynyl‐benzoic acid
series. According to the literature, the native ligand HI6 forms an
H‐bond (distance 2.14 Å) with Phe295 in the catalytic domain of
5HF9. Moreover, HI6 forms both π–π stacking and π–cation in-
teractions with Tyr124, Trp286, and Tyr341, and only π–π
stacking interaction with Trp72 (Figure S2). Additionally, the
interaction of this pharmacophore, which resides in the AChE,
reveals that 2,2‐dimethyl‐1,3‐dioxan‐4‐one‐substituted deriva-
tive 6f formed two H‐bond (distances: 1.99 and 2.67 Å) interac-
tions with Trp286 and Arg296 and hydrophobic interactions
with Tyr86 and Tyr337, and the docking scores of HI6
(molecular mechanics‐generalized Born surface area [MM‐GBSA]
value of −90.85 kcal/mol) and analog 6f (MM‐GBSA value of
−40.516 kcal/mol) are shown to be −13.59 and −8.03, respec-
tively. Furthermore, the most prominent residues accommodat-
ing hydrophobic fragments include Tyr86, Trp286, and Tyr337,
as well as Tyr72, Val73, Pro88, Tyr124, Val294, Phe295, Phe297,
Phe338, and Tyr341 (Figure 1).
The molecular understanding of the binding of 6I0L with the
macrodomain revealed that hCA I residues Phe91, Gln92, His94,
His96, Glu106, His119, Ala121, Leu131, Ala135, Leu141, Val143,
Ser197, Leu198, Thr199, His200, Pro202, Val207, and Trp209 act
as the critical amino acids in the binding site, which form mole-
cular interactions with GZH. In this direction, GZH, which is re-
ported as a natural ligand, and compound 6c (KI of 133.00 0.29 nM
for hCA I), which has the most potent inhibitory activity among the newly
methylene‐aminobenzoic acid and tetrahydroisoquinolynyl‐benzoic acid
analogs (4a–g and 6a–g), were analyzed in terms of contacts with hCA I.
The native ligand GZH forms two H‐bonds (distances: 1.91 and 1.93 Å)
with Thr199. Apart from this, GZH forms π–π interaction with His94.
Also, it plays a reference role as a Zn‐binding moiety with the hCA I
by forming a coordinate bond with Zn(II) ion (Figure S3). The 1,
3‐dimethyldihydropyrimidine‐2,4‐(1H,3H)‐dione‐substituted derivative of
tetrahydroisoquinolynyl‐benzoic acids (6c) formed two strong H‐bonds
(distances: 2.12 and 1.93 Å) with Gln92 and Thr199, respectively.
Meanwhile, hydrophobic interactions were observed between derivative
6c and Phe91, Ala121, Leu131, Ala132, Ala135, Val143, Leu198, Pro202,
Tyr204, and Trp209 (Figure 2). XP glide docking of analog 6c with the
active domain of 6I0L showed a higher docking score of −7.28 kcal/mol
and an MM‐GBSA value of −33.65 kcal/mol, compared with GZH
with a docking score of −6.39 kcal/mol and an MM‐GBSA value of
−17.37 kcal/mol.
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2.3.2
Molecular docking study
To better evaluate the molecular basis of the binding affinities
of the novel synthesized methylene‐aminobenzoic acid and
tetrahydroisoquinolynyl‐benzoic acid derivatives (4a–g and 6a–g),
the most efficient inhibitors 6c (C19H17N3O7), 6e (C19H17NO6),
and 6f (C19H19NO7) against the hCA I, II, and AChE were docked
into the active sites of these enzymes. The docking results
were compared with co‐crystallized natural ligands GZH
(C16H15ClF3N3O3S), GTQ (C7H6O4), and HI6 (C14H16N4O3) at the
binding sites of the receptors (6I0L, 4E3D, and 5HF9, respec-
tively). The molecular docking was performed using 6I0L (CA I
complexed with GZH, resolution of 1.40 Å, species: Homo sapiens),
4E3D (CA II complexed with GTQ, resolution of 1.60 Å, species:
Homo sapiens), and 5HF9 (AChE complexed with HI6, resolution of
2.20 Å, species: Homo sapiens). The green lines display hydrophobic
interactions, whereas the pink line exhibits the hydrogen bond
interaction. For validation of the in silico molecular docking pro-
cedure, the co‐crystalized ligands (GZH, GTQ, and HI6) in chain A
were extracted and redocked into the binding sites. To evaluate
the quality of the co‐crystallized ligands, their root mean square
deviation (RMSD) scores were computed. The results were
A further look into the crystallographic structural features
between 4E3D and native ligand GTQ revealed, is involved in two
H‐bonds (distances: 2.33 and 2.39 Å) with Thr199 and Thr200
residues, respectively (Figure S4). Figure 3 depicts the simulated
Kalayc?, Muharrem
