Design, synthesis, characterization, biological evaluation, and molecular docking studies of novel 1,2-aminopropanthiols substituted derivatives as selective carbonic anhydrase, acetylcholinesterase and α-glycosidase enzymes inhibitors

Article abstract of DOI:10.1080/07391102.2020.1811772

In the article, various substituted derivatives of 1,2-aminopropanthiol (1a–g) have been prepared by a general and efficient method, in one-steps, starting from available thiirane and aromatic amines (aniline, o-toluidine) as a convenient source of sulfur and nitrogen. The synthesized compounds were fully characterized by spectral and analytical data. Seven novel compounds are synthesized. The biochemical properties indicating their potential for constituting an anti-Alzheimer’s disease substance were also recorded revealing strong carbonic anhydrase I, and II, α-glycosidase, and acetylcholinesterase inhibitory effects. These synthesized novel 1,2-aminopropanthiols substituted derivatives (1a–g) were found to be effective inhibitors for the α-glycosidase, human carbonic anhydrase I and II, and acetylcholinesterase enzymes, with K_i values in the range of 11.47 ± 0.87–24.09 ± 6.37 μM for α-glycosidase, 29.30 ± 4.67-79.01 ± 4.49 μM for hCA I, 14.27 ± 2.82-30.85 ± 12.24 μM for hCA II and 5.76 ± 1.55–55.39 ± 2.27 μM for AChE, respectively. In the last step of this study, molecular docking calculations were obtained in order to compare the biological activities of indicated molecules against the enzymes of acetylcholinesterase, butyrylcholinesterase and α-glycosidase. Communicated by Ramaswamy H. Sarma.

Full text of DOI:10.1080/07391102.2020.1811772

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
Design, synthesis, characterization, biological
evaluation, and molecular docking studies of novel
1,2-aminopropanthiols substituted derivatives as
selective carbonic anhydrase, acetylcholinesterase
and α-glycosidase enzymes inhibitors
Afat Huseynova , Ruya Kaya , Parham Taslimi , Vagif Farzaliyev , Xadija
Mammadyarova , Afsun Sujayev , Burak Tüzün , Umit M. Kocyigit , Saleh
Alwasel & İlhami Gulçin
To cite this article: Afat Huseynova , Ruya Kaya , Parham Taslimi , Vagif Farzaliyev , Xadija
Mammadyarova , Afsun Sujayev , Burak Tüzün , Umit M. Kocyigit , Saleh Alwasel & İlhami
Gulçin (2020): Design, synthesis, characterization, biological evaluation, and molecular docking
studies of novel 1,2-aminopropanthiols substituted derivatives as selective carbonic anhydrase,
acetylcholinesterase and α-glycosidase enzymes inhibitors, Journal of Biomolecular Structure and
Dynamics, DOI: 10.1080/07391102.2020.1811772
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1811772
Design, synthesis, characterization, biological evaluation, and molecular docking
studies of novel 1,2-aminopropanthiols substituted derivatives as selective
carbonic anhydrase, acetylcholinesterase and a-glycosidase enzymes inhibitors
Afat Huseynovaa, Ruya Kayab,c, Parham Taslimid , Vagif Farzaliyeve, Xadija Mammadyarovae, Afsun Sujayeve,
f
g
h
c
_
€ €
Burak Tuzun , Umit M. Kocyigit , Saleh Alwasel and Ilhami Gulc¸in
b
aLaboratory of ‘Fine Organic Synthesis’ of Baku State University, Baku, Azerbaijan; Agri Ibrahim Cecen University Central Research and
c
d
€
Application Laboratory, Agri, Turkey; Faculty of Science, Department of Chemistry, Ataturk University, Erzurum, Turkey; Department of
e
Biotechnology, Faculty of Science, Bartin University, Bartin, Turkey; Laboratory of Theoretical Bases of Synthesis and Action Mechanism of
Additives, Institute of Chemistry of Additives, Azerbaijan National Academy of Sciences, Baku, Azerbaijan; Department of Chemistry, Faculty
of Science, Sivas Cumhuriyet University, Sivas, Turkey; Department of Basic Pharmaceutical Sciences, Division of Biochemistry, Faculty of
Pharmacy, Sivas Cumhuriyet University, Sivas, Turkey; Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
f
g
h
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 18 May 2020
Accepted 13 August 2020
In the article, various substituted derivatives of 1,2-aminopropanthiol (1a–g) have been prepared by a general
and efficient method, in one-steps, starting from available thiirane and aromatic amines (aniline, o-toluidine) as a
convenient source of sulfur and nitrogen. The synthesized compounds were fully characterized by spectral and
analytical data. Seven novel compounds are synthesized. The biochemical properties indicating their potential
for constituting an anti-Alzheimer’s disease substance were also recorded revealing strong carbonic anhydrase I,
and II, a-glycosidase, and acetylcholinesterase inhibitory effects. These synthesized novel 1,2-aminopropanthiols
substituted derivatives (1a–g) were found to be effective inhibitors for the a-glycosidase, human carbonic anhy-
KEYWORDS
Thiirane; aniline; 1,2-
aminopropanthiol; enzyme
inhibition; molecu-
lar docking
drase
I and II, and acetylcholinesterase enzymes, with Ki values in the range of 11.47
0.87–24.09 6.37 mM for a-glycosidase, 29.30 4.67-79.01 4.49 mM for hCA I, 14.27 2.82-30.85 12.24 mM for
hCA II and 5.76 1.55–55.39 2.27 mM for AChE, respectively. In the last step of this study, molecular docking cal-
culations were obtained in order to compare the biological activities of indicated molecules against the enzymes
of acetylcholinesterase, butyrylcholinesterase and a-glycosidase.
CONTACT Parham Taslimi
parham_taslimi_un@yahoo.com; ptaslimi@bartin.edu.tr
Faculty of Science, Department of Biotechnology, Bartin University,
Bartin 74100, Turkey
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
A. HUSEYNOVA ET AL.
have been proposed by the Third Asia-Pacific Region
Guidelines for Diabetes Treatment as the first treatment
method for reducing postprandial hyperglycemia (Li et al.,
2008; Yin et al., 2014). Various side effects of the currently
used drugs have made the discovery of new inhibi-
tors important.
In order to help the experimental studies, theoretical cal-
culations have been developed. Theoretical calculations of
the biological activities of the molecules will provide more
comprehensive information about the mechanisms involved
in the activities of these molecules. The most important fac-
tor in the interaction of molecules with enzymes is the
1. Introduction
Aminothiols are among the recently studied group of sulfur-
containing organic compounds. Aminothiol derivatives
exhibit a wide range of biological activities and can function
as potential medicinal molecules in the development of a
drug. In recent years, due interest has been allocated to
them in connection with their versatile use in medicine, as
well as intermediates of organic synthesis (Guillaume et al.,
2008). Aminothiols constitute an important class of com-
pounds for medicinal and synthetic chemistry. Some of them
(e.g. cysteine, homocysteine) are used as drugs in medicine.
The synthetic aminothiol, amifostine, was originally devel-
oped as a radioprotector and has been extensively used as a
chemical radioprotector for the normal tissues in cancer
radiotherapy and chemotherapy (Vijayaraghavan et al., 2009).
Aminothiols and their derivatives also exhibit a variety of
other physiological activity. These compounds can be used
to create blockers, autoimmunomodulators, antiseptics and
hypomicimic agents. They can serve as key compounds for
the synthesis of various nitrogen and sulfur-containing heter-
ocyclics, allowing them to be widely used as drugs in
pharmacological practice. Aminothiols are the sinton for fine
organic compounds in the making physiologically active
compounds (Maharramov et al., 2017).
€ €
chemical interactions (Tuzun, 2020). As these interactions
increase, the biological activities of the molecules increase
€ €
(Tuzun & Kaya, 2018). Accordingly, three enzymes that are
acetylcholinesterase for ID 4M0E (AChE) (Cheung et al.,
ꢂ
2013), Butyrylcholinesterase for ID 5NN0 (BChE) (Kosak et al.,
2017), a-glycosidase for ID 1R47 (a-Gly) (Tan et al., 2014),
were used to interact with the molecules. The probability of
using the studied molecules as medicines in the future has
been investigated.
2. Materials and methods
2.1. Measurements
Alzheimer’s disease (AD) occurs as a result of decreases in
neurotransmitters in the brain. The neurotransmitter which
exhibits the highest decreases in AD is also commonly
observed in dementia and other neurodegenerative diseases.
AD was found to be a dysfunction of memory. The decrease
in the level of acetylcholine (ACh) in the brain is the biggest
The purity of the synthesized compounds was determined
by paraphrase chromatography on a Tsvet-104 chromato-
graph, column 200 ꢀ 0.3 cm, temperature-210-P., the column
was purged with water vapor at a pressure of PH2O
¼
14709.98 ꢁ 19613.30. By the amount of sample supplied
0.1mkl. As the adsorbent, a 37% silicone brand elastomer
was used. ‘SE-301’ deposited on a solid carrier. Chromaton
‘N-AW’ C grain size 0.5 ꢁ 0.15 mm. TLC was performed on
Sulifol U-254 plates. Ethyl alcohol and hexane were used as
eluent in a ratio of 1:5. In all cases, the manifestation of iod-
ine vapor was formed by one spot. The chemical structure of
the synthesized compounds was confirmed by using IR, 1H,
13C NMR spectroscopy. The IR spectra were taken on the
instrument Nicolet IS-10. NMR experiments were performed
on a Bruker FT NMR spectrometer AVANCE 300 (300 MHz for
1H and 75 MHz for 13C) with BVT 3200 variable-temperature
unit in 5 mm sample tubes using Bruker Standard software
ꢀ
biochemical factor of this disease (Akıncıoglu et al., 2015;
€
Ekiz et al., 2018; Goc¸er et al., 2013; Kocyigit et al., 2017). A
comprehensive treatment of this disease has not been fully
developed. The treatments applied today are merely aiming
at alleviating the symptoms.
Acetylcholinesterase (AChE; E.C.3.1.1.7) is a nonspecific
enzyme that hydrolyzes lipolrophic ACh in tissues that is free
or in combination with phospholipids. AChE inhibitors such
as Rivastigmine, Galantamine and Donepezil are generally
used for this purpose (Akıncıoglu et al., 2015; Goc¸er et al.,
2015). Recent studies have reported that the amount of
butyrylcholinesterase (BChE; E.C.3.1.1.8) in the brains of
Alzheimer’s patients is higher than the amount in healthy
ꢀ
€
1
(Topspin 3.1). The H and 13C chemical shifts were referenced
ꢁ
brains (Massoulie et al., 1993). Therefore, it is estimated that
BChE inhibition may also be associated with AChE-inhibit-
ing drugs.
to internal tetramethylsilane (TMS).
It is believed that the control of postprandial hypergly-
cemia is important in the treatment of diabetes mellitus.
a-Glycosidase (E.C.3.2.1.20), secreted from the intestinal chori-
onic epithelium, is an enzyme responsible for the breakdown
of carbohydrates. In the 1980s, a-glycosidase inhibitors
emerged as a new class of antidiabetic drugs. These antidia-
betic drug class of a-glycosidase inhibitors slows down the
digestion and absorption process of carbohydrates by com-
petitively blocking a-glycosidase activity. As a result, the
peak concentration of postprandial blood glucose is reduced
and blood sugar levels are brought under control.
2.2. Synthesis of substituted 1,2-aminopropanthiols
(1a–g) general procedure
In a ampoule with a capacity of 100 mL was placed 15.8 g
(0.2 mol) aniline and 20.4 g (0.1 mol) of 1,2-epithio-3-hydroxy-
5,5,6,6-tetrafluorhexane. The ampoule was heated for 12 h in
a water bath. Then the ampoule ruptured, an excess of anil-
ine was distilled off, and the reaction product was subjected
to vacuum distillation. The extracts were combined with the
organic part, washed with warm water, dried with MgSO4,
then the solvent was distilled off and (9.9 g) 75% of com-
a-Glycosidase inhibitors may offer several advantages and pound (1a) was isolated by vacuum distillation. In a similar

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
way, other substituted 1,2-aminothiols (1b, 1c, 1d, 1e, 1f and NMR (75 MHz, CHCl3): 39.2, 56.5, 67.7, 70.6, 74.1, 113, 117,
1g) were obtained.
147.4. IR (KBr, t, cmꢁ1): 1120, 1365, 3340, 3050, 2540, 1445,
1510, 1610, 1570. Found, %: N ꢁ 5.24; S ꢁ 12.02. C15H23ONS.
Calculated (%): N ꢁ 5.28; S ꢁ 12.08.
2.2.1.
1-(P-Toluidino)-4,4,5,5-tetrafluoropentane-2-
thiol (1a)
20
Yield: 75%, b.p. 110–111 ꢂC/0.3 mm Hg, d4 ¼1.5050, Rf ¼ 2.2.6. 1-Phenoxy-3-(phenylamino)propane-2-thiol (1f)
20
0.47, 1H-NMR (CHCl3, 300 MHz): 2.5 (s, 1H - CH), 1.9 (d, 2H,
Yield: 60%, b.p. 111–112 ꢂC/0.3 mm, d4 ¼ 1.5480, Rf ¼ 0.29,
1H-NMR (CHCl3, 300 MHz): 1.93 (s, 3H, CH3), 2.19–2.51 (s,4H,
CH2), 5.69 (s, 1H – CHF2), 7.1-7.2 (s, 4H - Ar-H), 8.06 (s, 1H -
NH), 2.34 (s, 3H, CH3-Ph), 1.5 (s, 1H - SH). 13C-NMR (75 MHz,
2CH2), 8.02 (s, 2H, NH), 4.29 (s,1H, CH), 1.5 (s, 1H - SH);
6.82–7.27 (4H, m, Ar). IR (KBr, t, cmꢁ1): 3175, 3198, 3020,
CHCl3): 22.4, 24.3, 34.8, 60.5, 113.4, 114, 126.8, 129.8, 130.5,
144.6. IR (KBr, t, cmꢁ1): 1120–1110, 1365–1350, 3360–3340,
2978, 2240, 1620, 1604, 1445, 720, 680. Found, %: N ꢁ 6.19;
S ꢁ14.17. C11H15O2NS. Calculated %: N ꢁ 6.22; S ꢁ 14.22.
3050, 2545–2540, 1460–1445, 1510–1500, 1610–1590. Found,
%: N-5.18; S-11.94. C11H13F4NS. Calculated (%): N-5.24;
S-11.99.
2.2.7. 1-(P-Toluidino)-3-methoxypropane-2-thiol (1g)
20
Yield: 84%, b.p. 105–106 ꢂC/0.3 mm, d4 ¼ 1.5661, Rf ¼ 0.56,
1H-NMR (CHCl3, 300 MHz): 3.11 (s, 1H - CH), 3.19, 3.44, 3.51,
2.2.2. 1-(Phenylamino)-3-((tetrahydrofuran-2-yl)methoxy)-
3.76 (d, 2H, CH2), 6.31–6.84 (s, 4H - Ar-H), 1.5 (s, 1H - SH),
8.06 (s, 1H - NH), 2.32 (s, 3H, CH3-Ph), 3.24 (s, 3H, CH3O). 13C-
NMR (75 MHz, CHCl3): 24.3, 36.7, 56.8, 58.9, 76.8, 113.4, 126.8,
129.8, 144.6. IR (KBr, t, cmꢁ1): 1120–1110, 1365–1350,
3360–3340, 3050, 2545–2540, 1460–1445, 1510–1500,
1610–1590. Found, %: N, 6.56; S, 15.06. C11H18ONS.
Calculated (%): N ꢁ 6.60; S ꢁ 15.09.
propane-2-thiol (1b)
20
Yield: 65%, b.p. 95–96 ꢂC/0.2 mm Hg, d4 ¼1.5680, Rf ¼ 0.31,
1H-NMR (CHCl3, 300 MHz): 3.1 (s, 1H - CH), 6.58-7.08 (s, 4H -
Ar-H), 1.5 (s, 1H - SH), 8.06 (s, 1H - NH). 3.80; 3.70 (d, 2H-
CH2), 3.44, 3.19 (d, 2H-CH2), 3.76, 3.51 (d, 2H-CH2), 3.63; 3.38
(d, 2H-CH2), 3.80, 3.70 (d, 2H-CH2), 4.07 (t, 1H-CH), 1.90, 1.80
(d, 2H- CH2), 1.93; 1.68 (d, 2H-CH2). 13C-NMR (75 MHz, CHCl3):
25.9, 32.4, 37, 56.8, 71.2, 74.9, 75, 84.2, 113.5, 117.2, 147. IR
(KBr, t, cmꢁ1): 1115, 1355, 3365–3345, 3030, 2530,
1440–1425, 1515, 1605–1575. Found, %: N ꢁ 5.22; S ꢁ 11.95.
C14H21O2NS. Calculated (%): N ꢁ 5.24; S ꢁ 11.98.
2.3. Carbonic anhydrases, cholinesterase and
a-glycosidase inhibition
The inhibitory effect of novel 1,2-aminopropanthiols substi-
tuted derivatives (1a–g) on AChE activity was performed
according to spectrophotometric method of Ellman et al.
(1961) as described previously (Behcet et al., 2018).
a-Glycosidase inhibition effect of novel 1,2-aminopropan-
thiols substituted derivatives (1a–g) was evaluated according
to the method of Tao et al. (2013). The absorbance o sam-
ples were recorded at 405 nm (Taslimi et al., 2018).
In the present work, hCA I, and II isoenzymes were puri-
fied by Sepharose-4B-L-Tyrosine-sulfanilamide affinity column
chromatography, CA isoenzymes activity was determined
according to the spectrophotometric method of Verpoorte
et al. (1967) as described in details in our previous studies.
p-Nitrophenylacetate (p-NPA) was used as substrate for the
2.2.3. 1-(P-Toluidino)propane-2-thiol (1c)
20
Yield: 70%, b.p. 109–110 ꢂC/0.2 mm, d4 ¼ 1.5720, Rf ¼ 0.37,
1H-NMR (CHCl3, 300 MHz): 3.1 (s, 1H - CH), 6.58-7.08 (s, 4H -
Ar-H), 1.5 (s, 1H - SH), 8.06 (s, 1H - NH). 3.80; 3.70 (d, 2H-
CH2), 3.44, 3.19 (d, 2H-CH2), 3.76; 3.51 (d, 2H-CH2), 3.63, 3.38
(d, 2H-CH2), 3.80; 3.70 (d, 2H-CH2), 4.07 (t, 1H-CH), 1.90, 1.80
(d, 2H- CH2), 1.93, 1.68 (d, 2H-CH2). 13C-NMR (75 MHz, CHCl3):
31.4, 33.2, 34.1, 36.2, 60.8, 66.8, 113.5, 117.2, 129.6, 147.6. IR
(KBr, t, cmꢁ1): 1100, 1335, 3360, 2240, 1490, 1525,
1615–1570. Found, %: N ꢁ 5.38; S ꢁ 12.29. C15H17ONS.
Calculated (%): N ꢁ 5.41; S ꢁ 12.35.
€
enzymatic reaction (Turker et al., 2018). One CA enzyme unit
2.2.4.
1-(Phenylamino)-3-(tetrahydro-2H-pyran-4-yl)pro-
adopted the amount of CA, which had absorbance difference
at 348 nm over a 3 min at 25 ꢂC. For determination of inhib-
ition kinetics of novel 1,2-aminopropanthiols substituted
pane-2-thiol (1d)
20
Yield: 80%, b.p.: 96–97 ꢂC/0.2 mm, d4 ¼ 1.5660, Rf ¼ 0.56,
1H-NMR (CHCl3, 300 MHz): 2.7 (s, 1H - CH), 6.40-7.28 (s, 4H -
Ar-H), 1.5 (s, 1H - SH), 3.12 (s, 1H - NH), 1.28 (s, 3H- CH3). 13C-
NMR (75 MHz, CHCl3): 29, 54, 62, 72, 74, 113, 117, 129, 146.
IR (KBr, t, cmꢁ1): 3030, 3344, 2545–2540, 1610, 1590, 1510,
1500, 1460, 1445, 1334, 1125. Found, %: N ꢁ 7.69; S ꢁ 17.63.
C10H15NS. Calculated (%): N ꢁ 7.73; S ꢁ 17.68.
derivatives
(1a–g),
an
activity
(%)
and
[1,2-
Aminopropanthiols] graph was drawn. From these graphs,
half maximal inhibitor concentrations (IC50) for novel 1,2-ami-
nopropanthiols substituted derivatives (1a–g) were deter-
mined. Also, for Kis, three different concentrations of novel
1,2-aminopropanthiols substituted derivatives (1a–g) were
ꢀ
used (Yigit et al., 2018). Then, Lineweaver–Burk graphs were
2.2.5. 2-Mercapto-3-(phenylamino)propyl acetate (1e)
drawn according to these measurements (Lineweaver & Burk,
1934). Kis of novel 1,2-aminopropanthiols substituted deriva-
tives (1a–g) were determined from Lineweaver–Burk graphs
20
Yield: 78%, b.p. 75–76 ꢂC/0.1 mm, d4 ¼ 1.5242, Rf ¼ 0.48,
1H-NMR (CHCl3, 300 MHz): 2.87 (t, 1H - CH), 6.5–7.8 (s, 4H -
Ar-H), 1.5 (s, 1H - SH), 8.01 (s, 1H - NH), 3.9, 3.6 (d, 2H-CH2), as previously described (Aktas et al., 2020; Burmaoglu et al.,
3.24, 3.09 (d, 2H-CH2), 2.87 (d, 1H-CH), 2.05 (d, 1H-CH). 13C- 2020). Quantity of protein during the purification processing,

4
A. HUSEYNOVA ET AL.
Bradford’s technique was utilized (Bradford, 1976), and
bovine serum albumin was used as the standard protein
(Gulc¸in et al., 2018). Sodium dodecyl sulphate-polyacrylamide
gel electrophoresis was employed for visualizing the image
of isoenzymes (Atmaca et al., 2018).
3. Results and discussion
3.1. Chemistry
There are certain fundamental and applied issues in science
that have not been justified merely by approaches limited to
one scientific field, and for many years, satisfactory results
have not been achieved. There is a need for a comprehen-
sive scientific approach to such issues, and the most success-
ful scientific results of the recent years are reflected in the
research findings that science has gained through multidis-
ciplinary (interdisciplinary) approaches.
From this point of view, this new research article focuses
on the modern problems common to medicine and other
related fields—biological activity (Taslimi et al.). Potentially
such problems occur in the environment which practically
include organisms. In this regard, the expansion of scientific
studies on the study of new synthesis methods of both anti-
oxidant and biological active compounds with combined
effects is of great importance.
According to literature (Karimov et al., 2020; Mammadov
et al., 2019), aminothiol derivatives exhibit a wide biological
activity and can function as potential medical molecules in
the development of potential drugs. It was shown that het-
erocyclic compounds containing nitrogen and sulfur are
effective antimicrobial and antioxidant additives. For this pur-
pose, in continuation of research in the field of the synthesis
of aminothiols, the new 1,2-aminopropanthiols (1a–g)
belonging to new and more effective antioxidants were syn-
thesized for the first time.
2.4. Docking studies
Theoretical studies are widely used to comment on the bio-
logical activities of molecules. In this study, the activities of
molecules against enzymes were compared. For this com-
parison, the molecules were first optimized using the
Gaussian package program with HF/6-31þþg basis set
(Frisch et al., 2009). After optimizing structures of 1,2-amino-
ꢃ
propanthiol derivatives, files with the .sdf extension were
created. In the next process, it was calculated by using
Maestro Molecular Modeling platform (version 12.2) by
€
Schrodinger, LLC (Schrodinger, 2019) to examine the interac-
tions of molecules and enzymes. This program consists of
many modules. In the first module, enzymes, which are
Human Acetylcholinesterase for ID 4M0E (AChE) (Cheung
ꢂ
et al., 2013), Butyrylcholinesterase for ID 5NN0 (BChE) (Kosak
et al., 2017), a-Glycosidase for ID 1R47 (a-Gly) (Tan et al.,
2014), were prepared for interaction with molecules by the
protein preparation module (Friesner et al., 2006;
Schrodinger, 2019). With the help of this module, water mol-
ecules in the structure of enzymes were removed, and then
the loads and binding methods of the enzymes were charac-
terized. A grid box of default size (20 ꢀ 20 ꢀ 20 Å3) of the
protein structure was centered on 1,2-aminopropanthiol
derivatives position. A minimization of the protein of the
enzymes was performed using the default constraint of 0.30
RMSD (root-mean-squared deviation) and the OPLS3e force
field. The active sites of the enzyme were then determined
using this module. Small proteins in this active region were
given freedom of movement for interactions. In the next
step, 1,2-aminopropanthiol derivatives were used to prepare
for interaction the LigPrep module (Sastry et al., 2013;
Schrodinger, 2019). Physiological pH values of high-energy
isomers of 1,2-aminopropanthiol derivatives were deter-
mined. The Glide ligand was interacted with the docking
module (Taslimi et al., 2020) to interact with prepared 1,2-
aminopropanthiol derivatives and enzymes. Function score of
the glide ligand was selected as the default.
The reaction is carried out in an aqueous medium accord-
ing to the Scheme 1.
1,2-Aminothiols (1a–g) were obtained by reacting various
thiiranes with aromatic amines-aniline, o-toluidine at a ratio of
reactants thiirane: amine (1:2) for 12 h at 90–100 ꢂC in ampoule.
The yield of substituted 1,2-aminothiols was 60–84%.
Synthesized 1,2-aminothiols (1a–g) were colorless liquids.
When storing, the liquid turned yellow. They are insoluble in
water, dissolve well in organic solvents (acetone, ether, ethanol,
etc.) and have a high boiling point and thermal stability, that is,
along with other operational properties, they are also thermally
stable. The physicochemical characteristics, the data of elemen-
tal analysis and molecular refraction of the esters (1a–g) were
given in the corresponding description of the experiment. The
purity of the synthesized 1,1-aminothiols (1a–g) was confirmed
by elemental analysis, thin-layer and gas-liquid chromatog-
raphy, and the structure of the compounds was proved by IR,
1H, and 13C NMR spectroscopies. IR and NMR spectra were
recorded on a Bruker spectrophotometer.
The probability of using the studied molecules as medi-
cines in the future has been investigated. For this study,
ADME analysis (Absorption, distribution, metabolism, excre-
tion and toxicity) of the molecules was performed. The Qik-
€
€
prop module (Schrodinger, 2020) of the Schrodinger software
of molecules was used for ADME analysis. As a result of cal-
culations made with The Qik-prop module, many parameters
of the molecules were obtained. The numerical values of
these parameters have provided a lot of information about
their ability to be medicines (Zengin et al., 2018). The ability
of 1,2-aminopropanthiol derivatives to be used as drugs
depends on the numerical values of these parameters in a
certain range.
3.2. Biochemical studies
The CA isoenzymes inhibitors are utilized to design novel
classes of drugs for glaucoma and epilepsy (Sujayev et al.,
2018). Additionally, novel CA inhibitors have been required
to expand as therapeutic factors. Some researchers have
studied the inhibition of hCAs with catecholamines, thiourea
derivatives, bromophenols, anions, uracil derivatives and sul-
phonamides (Taslimi et al., 2017). In addition, chalcones and

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Scheme 1. Derivatives of substituted 1,2-aminopropanthiols (1a–g).
pyrazoles have also been studied to inhibit hCAs. The results order: 1g (16.78 mM, r2: 0.9716) < 1e (19.69 mM, r2: 0.9825) <
presented in Table 1 indicate that novel 1,2-aminopropan- 1c (23.49 mM, r2: 0.9858) < 1b (26.35 mM, r2: 0.9546) < AZA
thiols substituted derivatives (1a–g) had effective inhibition (148.78 mM, r2: 0.9545).
The enzyme can be inactivated by various inhibitors, lead-
ing to ACh accumulation and also disrupted neurotransmis-
sion caused by hyperstimulation of muscarinic and nicotinic
receptors (Gulc¸in et al., 2017; Maharramov et al., 2019).
Reversible AChE inhibitors are extensively utilized for the
treatment of neurodegenerative diseases, while irreversible
inhibitors are associated with toxic effects. Indeed, irrevers-
ible AChE inhibitors (AChEIs) include chemical warfare factors
and many organophosphorus molecules used as insecticides
against hCA I isoform. The hCA I isoform was inhibited by
novel 1,2-aminopropanthiols substituted derivatives (1a–g) in
nanomolar levels, the Ki of which obtained between
29.30 4.67 and 79.01 4.49 mM. Indeed, acetazolamide
(AZA), as a broad-specificity CA inhibitor showed Ki value of
136.48 11.87 mM against hCA I. Among the inhibitors, 1b
and 1g were observed to be the effective hCA I inhibitors
with Ki of 29.30 4.67 and 38.77 5.88 mM, respectively. The
hCA I inhibition effects of novel 1,2-aminopropanthiols sub-
stituted derivatives (1a–g) were found to be the greater than
AZA. For hCA I, IC50 values of AZA as positive control and
some novel 1,2-aminopropanthiols substituted derivatives
(1a–g) were as the following order: 1g (24.66 mM, r2: 0.9965)
< 1c (31.94 mM, r2: 0.9906) < 1a (36.67 mM, r2: 0.9417) < 1b
€
ꢀ
and pesticides (Turkan et al., 2018; Yigit et al., 2018). All of
novel 1,2-aminopropanthiols substituted derivatives (1a–g)
had significantly higher AChE inhibitory activity than tacrine
as control molecule. Furthermore, the Ki values of novel 1,2-
aminopropanthiols substituted derivatives (1a–g) and tacrine
(37.46 mM, r2: 0.9485) < AZA (112.54 mM, r2: 0.9240). Against are summarized in Table 1. As can be observed from the
the hCA II isoform, the novel 1,2-aminopropanthiols substi- results recorded in Table 1 and Figure 1, novel 1,2-aminopro-
panthiols substituted derivatives (1a–g) effectively inhibited
tuted derivatives (1a–g) demonstrated varying Ki values from
14.27 2.82 to 30.85 12.24 mM (Table 1). These novel 1,2- AChE, with Ki values in the range of 5.76 1.55 to
aminopropanthiols substituted derivatives (1a–g) were 55.39 2.27 mM. Thus, all of these novel compounds had
observed to have high inhibition effects toward hCA II. almost similar inhibition profiles. The most active 1e and 1c
Additionally, AZA showed Ki of 170.64 25.76 mM against showed Ki values of 5.76 1.55 and 10.13 3.74 mM. For
hCA II. 1a and 1c exhibited the highest inhibition effect with AChE, IC50 values of TAC (Tao et al., 2013) and some novel
Ki values of 14.27 2.82 and 16.69 1.60 mM, respectively. For 1,2-aminopropanthiols substituted derivatives (1a–g) are as
hCA II, IC50 values of AZA and some novel 1,2-aminopropan- the following order: 1g (25.48 mM, r2: 0.9825) < 1a (27.50 mM,
thiols substituted derivatives (1a–g) are as the following r2: 0.9965) < 1b (31.79 mM, r2: 0.9578) < TAC (70.87 nM, r2:

6
A. HUSEYNOVA ET AL.
Table 1. Inhibition results of novel 1,2-aminopropanthiols (1a–g) derivatives on carbonic anhydrase, acetylcholinesterase and a-glycosidase enzymes.
IC50 (mM)
Ki (mM)
Compounds
hCA I
r2
hCA II
r2
AChE
r2
a-Gly
r2
hCA I
hCA II
AChE
a-Gly
1a
1b
1c
1d
1e
1f
1g
AZA
TAC
36.67
37.46
31.94
49.5
38.72
37.56
24.66
112.54
–
0.9417
0.9485
0.9906
0.9593
0.9947
0.9704
0.9965
0.9240
–
31.5
26.35
23.49
50.58
19.69
33.00
16.78
148.78
–
0.9657
0.9546
0.9858
0.9447
0.9825
0.9963
0.9716
0.9545
–
27.50
31.79
44.71
60.37
52.50
50.22
25.48
–
0.9965
0.9578
0.9706
0.9487
0.9508
0.9958
0.9825
40.52
40.06
42.00
50.58
27.83
31.64
14.90
–
0.9835
0.9857
0.9938
0.9446
0.9835
0.9786
0.9897
–
40.18 11.89
29.30 4.67
47.41 2.74
56.35 17.87
45.30 17.59
79.01 4.49
38.77 5.88
136.48 11.87
14.27 2.82
17.53 6.42
16.69 1.60
26.85 5.76
24.20 3.96
30.85 12.24
20.13 3.41
170.64 25.76
33.23 7.85
22.62 1.70
10.13 3.74
55.39 2.27
5.76 1.55
42.59 1.75
20.41 0.25
–
19.30 7.60
15.02 3.48
15.72 2.25
24.09 6.37
22.21 3.37
11.47 0.87
17.08 3.50
–
*
**
70.87
0.9549
–
–
57.90 7.63
–
Figure 1. Determination of Lineweaver–Burk graphs for excellent inhibitors of alpha glycosidase and AChE enzymes.
Table 2. Numerical values of the parameters obtained from interaction of studied molecule with enzymes.
1a
1b
1c
1d
1e
1f
1g
AChE
a-Gly
hCA I
hCA II
Docking score
Glide ligand efficiency
Glide h-bond
Glide evdw
ꢁ5.35
ꢁ0.31
ꢁ0.46
ꢁ23.25
ꢁ5.02
ꢁ36.29
ꢁ3.99
ꢁ0.23
ꢁ0.30
ꢁ19.01
ꢁ7.45
ꢁ33.08
ꢁ7.64
ꢁ0.45
ꢁ0.12
ꢁ18.47
ꢁ7.94
ꢁ51.76
ꢁ5.79
ꢁ0.34
ꢁ0.19
ꢁ15.30
ꢁ11.16
ꢁ45.08
ꢁ6.73
ꢁ0.37
ꢁ0.32
ꢁ31.46
ꢁ4.45
ꢁ45.02
ꢁ4.05
ꢁ0.23
ꢁ0.58
ꢁ23.86
ꢁ7.04
ꢁ35.98
ꢁ7.57
ꢁ0.42
ꢁ0.21
ꢁ18.48
ꢁ9.94
ꢁ64.13
ꢁ7.02
ꢁ0.39
ꢁ0.63
ꢁ18.89
ꢁ9.88
ꢁ51.23
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
ꢁ6.27
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
ꢁ0.57
ꢁ0.57
ꢁ21.32
Glide ecoul
ꢁ2.63
Glide emodel
Docking Score
Glide ligand efficiency
Glide h-bond
Glide evdw
ꢁ32.93
–
–
–
ꢁ3.66
ꢁ0.20
ꢁ0.33
ꢁ19.50
ꢁ8.57
ꢁ32.08
ꢁ7.50
ꢁ0.42
ꢁ0.13
ꢁ18.52
ꢁ7.98
ꢁ55.53
–
ꢁ4.17
ꢁ0.28
ꢁ0.29
ꢁ21.15
ꢁ10.14
ꢁ40.15
ꢁ5.22
ꢁ0.35
ꢁ0.32
ꢁ25.24
ꢁ5.92
ꢁ48.59
–
ꢁ4.10
–
–
–
–
–
–
–
–
–
ꢁ0.29
ꢁ0.57
ꢁ18.85
Glide ecoul
ꢁ9.98
Glide emodel
Docking Score
Glide ligand efficiency
Glide h-bond
Glide evdw
ꢁ35.31
–
–
–
–
–
–
–
–
–
–
–
–
Glide ecoul
–
–
Glide emodel
Docking Score
Glide ligand efficiency
Glide h-bond
Glide evdw
–
ꢁ1.06
ꢁ0.06
ꢁ0.07
ꢁ31.61
ꢁ4.43
ꢁ49.75
ꢁ6.33
ꢁ0.58
ꢁ0.38
ꢁ11.83
ꢁ10.39
ꢁ43.32
–
–
–
–
–
–
–
–
Glide ecoul
Glide emodel
–
–

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
Figure 2. Demonstration of interactions between AChE enzyme and molecule with highest biological activity.
Figure 3. Demonstration of interactions between a-Glycosidase enzyme and molecule with highest biological activity.
0.9549). Like donepezil, AChEIs are approved by the Food inhibitors are utilized to treat mainly voglibose, acarbose
and Drug Administration in the United States for the treat-
ment of AD, and have clinical trial data supporting their use
in Parkinson’s disease and vascular dementia.
and miglitol.
3.3. Docking results
For a-glycosidase enzyme, novel 1,2-aminopropanthiols
substituted derivatives (1a–g) have IC50 values in the range
In the interaction of 1,2-aminopropanthiol derivatives with
enzymes, some sections are left blank in Table 2. It was seen
that the molecules in these empty sections have no inter-
action with enzymes. Therefore, these sections were left
blank. The interactions are the most important factors affect-
of
14.90–50.58 mM
and
Kis
in
the
range
of
11.47 0.87–24.09 6.37 mM (Table 1). For this enzyme, the
most effective Ki values of 1f and 1b were with Ki values of
11.47 0.87 and 15.02 3.48 mM, respectively. For a-glycosi-
dase, IC50 values of acarbose as positive control and some
novel 1,2-aminopropanthiols substituted derivatives (1a–g)
are as the following order: 1g (14.90 mM, r2: 0.9897) < 1e
(27.83 mM, r2: 0.9835) < 1f (31.64 mM, r2: 0.9786) < ACR
(56.44 mM). Inhibition of a-glycosidases by inhibitors tends to
slow the breakdown and release of sugar molecules into the
bloodstream and can be utilized as therapeutic factors in the
€
€
€
ing the biological activity of molecules (Sayin & ungordu,
2018, 2019; Sayin & karakas¸, 2018a, 2018b). These interac-
tions have many different types of interactions such as
hydrogen bonds, polar and hydrophobic interactions, p–p
and halogen bonds (Jayarajan et al., 2020; Sayin & Karakas¸,
€
€
€
2017; Sayin & Ungordu, 2019). As these interactions between
therapy of obesity and diabetes. Indeed, some of the the molecule and the enzyme increase, the biological activity

8
A. HUSEYNOVA ET AL.
Figure 4. (a) Demonstration of interactions between hCA I enzyme and molecule with highest biological activity. (b) Demonstration of interactions between hCA I
enzyme and molecule with highest biological activity.
€ €
of the molecule increases (Mamedova et al., 2019; Tuzun & there is more than one stable isomer of a molecule in the
Saripinar, 2020). There are many small protein molecules in preparation process of the molecules. In docking calculations,
enzymes. Since these proteins are composed of heteroatoms, these isomers can dock at different points in the active
they can form strong interactions. These interactions with region of proteins. When these dockings are sorted accord-
molecules are shown in Figures 2–5. In the calculations ing to the numerical values of the Docking score parameter,
made, the number of poses consisting of the interactions of only the most negative value is considered. Therefore, even
enzyme’s protein and molecules is 35.
if a molecule in docking has different isomers at different
In molecular docking calculations, these parameters are points, only the most negative isomer is considered. As a
used to explain the biological activities of molecules against result of the calculations, the most negative value of the
enzymes. A comparison of the biological activity of mole- docking score parameter against all enzymes is, respectively,
cules is made according to the numerical values of these the hCA I isoenzymes for the 1a molecule, the hCA II isoen-
parameters, among which the most important parameter is zymes for the 1b molecule, the AChE enzymes for the 1b
the docking score (Subhani et al., 2015). The biological activ- molecule, and the a-glycosidase enzymes for the 1f mol-
ity of this molecule, which is the numerically most negative ecule. Another parameter is docking model, which is the
molecule, is generally the highest. In the calculations made, energy numerical value of the interaction pose between the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Figure 4. Continued.
Figure 5. Demonstration of interactions between hCA II enzyme and molecule with highest biological activity.
molecule and the enzyme. Glide ligand efficiency parameter molecule 1f, between carbonyl oxygen and GLH203, ARG227,
gives information about the effectiveness of molecules. The and LYS168 proteins. Again, a hydrogen bond is formed
Glide h-bond parameter of 1,2-aminopropanthiol derivatives between the hydrogen atom attached to the sulfur atom in
predicts the number of hydrogen bonds formed between the 1f molecule and the ASP231 protein. Pi–pi stacking
molecules and enzymes. The Glide evdw parameter gives occurs between the enzyme hCA I and the molecule 1a,
information about the number of Van der Waals interactions between the benzene ring and the HIS94 and HIE64 proteins.
resulting from the interaction (Sever et al., 2019). The Glide Plus, the salt-bridge interaction occurs between the sulfur
ecoul parameter predicts Coulomb interactions that occur in atom and the ZN261 protein. These interactions are shown
the interaction of 1,2-aminopropanthiol derivatives with in more detail in Figure 4a, b. In this docking study, the
enzymes (Wang et al., 2019). These parameters are used to numerical value of the docking score between this molecule
explain the interactions of molecules with enzymes and also and this enzyme is the most negative. Finally, pi–pi stacking
used to compare the biological activities of 1,2-aminopropan- occurred between the hCA II enzyme and the molecule 1b,
thiol derivatives.
between the benzene ring and the HIS94 enzyme. A hydro-
As a result of docking calculations, many interactions gen bond interaction occurred between the tetrahydrofuran
occur between molecules and enzymes. In the AChE enzyme, ring and GLN92. Salt bridge interaction occurs between sul-
a hydrogen bond interaction occurs between the O atom in fur atom and ZN265 protein.
the center of the 1b molecule and the TYR124 protein.
After interactions of 1,2-aminopropanthiol derivatives with
Hydrophobic interactions with the enzyme occurs in the enzymes, the future drug properties of these derivatives
tetrahydrofuran ring side of the molecule. However, hydro- were investigated. For this, ADME analysis of 1,2-aminopro-
gen bonding occurs between the a-Gly enzyme and the panthiol derivatives was performed. Many parameters of 1,2-

10
A. HUSEYNOVA ET AL.
Table 3. ADME properties of molecules.
1a
1b
1c
1d
1e
1f
1g
Reference range
Solute Molecular Weight
Solute Dipole Moment (D)
Solute Total SASA
Solute Hydrophobic SASA
Solute Hydrophilic SASA
267
2.1
483
86
10.8
202
184
797
1.8
1.5
0.9
24
7.0
267
4.1
259
3.8
546
62
10.8
407
66
913
1.8
2.3
0.8
30
10.4
13.5
7.2
167
1.9
265
3.5
225
7.2
211
3.6
130–725
1.0–12.5
300–1000
0–750
7.0–330
0–450
0–175
500–2000
0.0–6.0
562
284
10.8
202
66
944
1.8
4.9
0.8
28
9.3
405
121
10.8
202
71
641
1.8
1.5
0.9
19
6.5
574
295
10.8
202
65
973
1.8
3.2
0.8
30
9.5
481
130
81.5
202
67
792
1.8
3.5
0.9
24
8.4
479
255
10.8
146
67
782
1.8
3.2
0.9
23
7.4
Solute Carbom Pi SASA
Solute Weakly Polar SASA
Solute Molecular Volume (A3)
Solute as Donor-Hydrogen Bonds
Solute as Acceptor-Hydrogen
Solute Globularity (Sphere ¼1)
QP Polarizability (A3)
2.0–20.0
0.75–0.95
13.0–70.0
4.0–18.0
8.0–35.0
4.0–45.0
ꢁ2 to 6.5
ꢁ6.5 to 0.5
ꢁ6.5 to 0.5
QP log p for hexadecane/gas
QP log p for octanol/gas
QP log p for water/gas
QP log p for octanol/water
QP log S aqueous solubility
QP log S-conformation indepent
LogHERG
Apparent Caco-2 Permeability (nm/sec)
QP log BB for brain/blood
Apparent MDCK Permeability (nm/sec)
QP log Kp for skin Permeability (Jm)
Solute Ionization Potential (eV)
Solute Electron Affinity (eV)
No. of Primary Metabolites
QP log K has Serum protein Binding
Qual. Model for Human Oral Absorption
% Human Oral Absorption in Gl ( 20%)
Solute CdW Polar SA (PSA)
Lipinski Rule of 5 Violations
Jorgensen Rule of 3 Violations
11.2
5.2
4.3
14.1
8.2
3.5
9.1
5.4
2.9
13.8
6.8
4.3
12.8
7.6
2.6
11.2
6.4
3.1
4.5
ꢁ4.1
ꢁ4.2
ꢁ4.8
7818
0.6
10000
ꢁ0.4
9.4
0.3
4
0.1
3
ꢁ3.7
ꢁ3.1
ꢁ5.3
7818
0.1
10000
ꢁ0.2
9.0
ꢁ4.4
ꢁ4.2
ꢁ6.2
7818
0.2
10000
0.4
9.1
0.0
5
0.3
ꢁ2.5
ꢁ2.2
ꢁ4.3
7818
0.4
10000
ꢁ0.6
9.2
ꢁ4.6
ꢁ3.6
ꢁ5.3
7818
0.2
10000
ꢁ0.3
9.0
ꢁ3.1
ꢁ2.7
ꢁ4.7
1669
ꢁ0.4
1993
ꢁ1.7
9.3
ꢁ3.1
ꢁ2.6
ꢁ4.5
7818
0.3
10000
ꢁ0.6
9.0
(corcern below ꢁ5)
a
ꢁ3 to 1.2
a
Kp in cm/h
7.9–10.5
0.9–1.7
ꢁ0.1
0.0
4
ꢁ0.1
0.2
4
ꢁ0.1
6
4
6
1.0–8.0
ꢁ0.1
3
100
28.8
0
ꢁ0.2
0.3
3
100
19.7
0
ꢁ0.2
ꢁ0.2
3
100
20.7
0
ꢁ1.5 to 1.5
3
3
3
–
b
100
12.6
0
100
20.3
0
100
12.6
0
100
54.0
0
7–200
Maximum is 3
Maximum is 3
0
0
0
0
0
0
0
a<25 is poor and >500 is great.
b<25% is poor and >80% is high.
aminopropanthiol derivatives were obtained from ADME ana-
lysis in Table 3. These parameters provide information on the
ability of 1,2-aminopropanthiol derivatives to be employed
as drugs. The numerical values of these parameters are
expected to be within a certain range. If the numerical val-
ues of the parameters are outside these ranges, 1,2-amino-
propanthiol derivatives are not expected to be used as drugs
in the future. Among these parameters; there are many
4. Conclusion
In conclusion, 1,2-aminopropanthiol exhibits a wide biological
activity and can function as potential medical molecules in the
development of a drug. In this study, the derivatives of 1,2-
aminopropanthiol (1a–g) were prepared with thiirane com-
pounds with aromatic amines. Especially, the evaluation of the
inhibitory efficacy of compound 1e against acetyl and butyryl-
cholinesterase enzymes also indicates the anti-AD potential.
The results were remarkably striking because of the much
stronger inhibitory effect compared to standard drugs. In view
of the obtained molecular docking results, the biological activ-
ity values of the molecules against the enzymes were found to
be consistent with the experimental results. Interactions
between molecule and enzyme were the most important fac-
tors affecting biological activity values. Additionally, antidia-
ꢀ
parameters such as Solute Molecular Weight (Saglık et al.,
ꢀ
2019), Solute CdW Polar SA, logHERG (Saglık et al., 2019),
Apparent Caco-2 Permeability, QP log BB for brain/blood
(Ertas et al., 2019), Apparent MDCK Permeability, Lipinski
Rule of 5 Violations (Gunduz et al., 2020), Jorgensen Rule of
3 Violations (Jorgensen & Duffy, 2002; Lipinski et al., 1997),
etc. These parameters provide information on how 1,2-ami-
nopropanthiol derivatives behave in human metabolism. The
Solute Molecular Weight parameter gives information about betic and anticholinergic properties of these compounds were
the weights of molecules. The Solute CdW Polar SA param-
eter is Van der Waals surface area of polar nitrogen and oxy-
gen atoms and carbonyl carbon atoms. The logHERG
parameter is IC50 value for blockage of HERG Kþ Channel.
Apparent Caco-2 Permeability parameter is Caco 2 cells con-
stitute a model for the gut-blood barrier. The QP log BB for
brain/blood parameter is Predicted brain/blood partition
coefficient for orally delivered drugs. Apparent MDCK
Permeability parameter is MDCK cells are considered to be a
good mimic for the blood–brain barrier. Lipinski Rule of 5
Violations and Jorgensen Rule of 3 Violations is a combin-
ation of many parameters.
determined in this study.
Acknowledgements
This research was made possible by TUBITAK ULAKBIM, High
Performance and Grid Computing Center (TR-Grid e-Infrastructure). S.
Alwasel would like to extend his sincere appreciation to the Researchers
Supporting Project (RSP-2019/59), King Saud University, Saudi Arabia, for
support. This work was carried out with the support of the Science
Development Fund under the President of Azerbaijan Republic-EIF/GAM-
4-BGM-GIN-2017-3(29)-19/05/4-M-07.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
11
scoring incorporating a model of hydrophobic enclosure for protein-
ligand complexes. Journal of Medicinal Chemistry, 49(21), 6177–6196.
https://doi.org/10.1021/jm051256o
Disclosure statement
The authors declare that there are no conflicts of interest.
Frisch, M., Trucks, G., Schlegel, H., Scuseria, G., Robb, M., Cheeseman, J.,
Scalmani, G., Barone, V., Mennucci, B., Petersson, G., Nakatsuji, H.,
Caricato, M., Li, X., Hratchian, H., Izmaylov, A., Bloino, J., Zheng, G.,
Funding
Sonnenberg, J., Hada, M.,
… Fox, D. (2009). Gaussian 09, Revision
This work is supported by the Scientific Research Project Fund of Sivas
Cumhuriyet University under the project number RGD-020.
D.01. Wallingford, CT: Gaussian, Inc.
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Parham Taslimi
http://orcid.org/0000-0002-3171-0633
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