Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones

Article abstract of DOI:10.1016/j.bbrc.2016.11.082

Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC₅₀ of 0.16?±?0.008?μM and 2m in 2-pyrazoline chalcones with IC₅₀ of 0.13?±?0.006?μM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and?≈?173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC₅₀?±?SEM?=?22.2?±?3.2?μM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.

Full text of DOI:10.1016/j.bbrc.2016.11.082

Accepted Manuscript
Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-
pyrazoline derivatives of chalcones
Muhammad Shakil Shah, Shafi Ullah Khan, Syeda Abida Ejaz, Saifullah Afridi, Syed
Umar Farooq Rizvi, Muhammad Najam-ul-Haq, Jamshed Iqbal
PII:
S0006-291X(16)31945-3
10.1016/j.bbrc.2016.11.082
YBBRC 36786
DOI:
Reference:
To appear in: Biochemical and Biophysical Research Communications
Received Date: 9 November 2016
Accepted Date: 14 November 2016
Please cite this article as: M.S. Shah, S.U. Khan, S.A. Ejaz, S. Afridi, S.U.F. Rizvi, M. Najam-ul-Haq, J.
Iqbal, Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline
derivatives of chalcones, Biochemical and Biophysical Research Communications (2016), doi: 10.1016/
j.bbrc.2016.11.082.
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Graphical Abstract
Cholinesterases Inhibition and Molecular Modeling Studies of Piperidyl-thienyl and 2-
pyrazoline Derivatives of Chalcones
Muhammad Shakil Shah, Shafi Ullah Khan, Syeda Abida Ejaz, Saifullah Afridi, Syed Umar
Farooq Rizvi, Muhammad Najam-ul-Haq, Jamshed Iqbal
Binding orientation of active compounds and co-crystalized ligand within active site of target
enzyme

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Cholinesterases Inhibition and Molecular Modeling Studies of Piperidyl-
thienyl and 2-pyrazoline Derivatives of Chalcones
Muhammad Shakil Shaha,b, Shafi Ullah Khana, Syeda Abida Ejaza, Saifullah Afridia, Syed Umar
Farooq Rizvic, Muhammad Najam-ul-Haqb, Jamshed Iqbala*
aCentre for Advanced Drug Research, COMSATS Institute of Information Technology,
Abbottabad-22060, Abbottabad, Pakistan.
bDivision of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya
University, 60800, Multan, Pakistan.
cInstitute of Chemistry, University of the Punjab, Lahore, Pakistan.
Abstract
Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various
neurological problems most precisely Alzheimer’s disease (AD), which leads to senile dementia.
Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the
treatment of Alzheimer’s disease. FDA approved drugs for the treatment of AD, belong to a group of
cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease
progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential.
For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for
their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective
inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16±0.008 µM and
2m in 2-pyrazoline chalcones with IC50 of 0.13±0.006 µM, were found to be the most potent inhibitors of
AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor
i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Molecular docking studies of most potent inhibitors
were carried out to investigate the binding interactions inside the active site. Molecular docking study
revealed that potent compounds and co-crystalized ligand had same binding orientation within the active
site of target enzyme. Most of these compounds are selective inhibitors of AChE that can be to use
against progressive neurodegenerative disorder and age related problems in near future.
Key words: Alzheimer’s disease, cholinesterases inhibitors, piperidyl-thienyl derivatives, 2-pyrazoline
derivatives of chalcones, molecular docking.
Correspondence: Prof. Dr. Jamshed Iqbal, Centre for Advanced Drug Research, COMSATS Institute of
Information Technology, Abbottabad, Postal Code 22060, Pakistan, Tel: +92-992-383591-96, Fax: +92-
992-383441, E-Mail: drjamshed@ciit.net.pk / jamshediqb@googlemail.com

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1. Introduction
Cholinesterases (ChEs) belong to a supper family of esterase/lipase enzyme that catalyze the hydrolysis of
a neurotransmitter acetylcholine (ACh) into choline and acetic acid and thus terminate the cholinergic
neurotransmission [1]. This catalytic reaction plays an important role to allow a cholinergic neuron to
come back into its resting state after activation. Mostly present in cholinergic and non-cholinergic tissues
and other body fluids including plasma [2]. On the basis of substrate specificity and inhibitors, two types
of cholinesterase co-exist simultaneously throughout the body; acetylcholinesterase and
butyrylcholinesterases [3]. Both these forms are highly homologous i.e., > 65% but are products of
different genes on the chromosomes 7 and 3 in case of human, respectively [4]. Acetylcholinesterase
(AChE; E.C. 3.1.1.7) is a membrane- bound enzyme found in many types of conducting tissues; nerve
and muscle, cholinergic and non-cholinergic fibers, central and peripheral tissues, sensory and motor
neuron fibers while butyrylcholinesterase (BChE; E.C.3.1.1.8), also called plasma cholinesterase or
pseudo- cholinesterase is mainly distributed in the liver, intestine, heart and lungs [5,6]. The main
biological role of AChE is the termination of impulse transmission by quick hydrolysis of the cationic
neurotransmitter acetylcholine [7] while BChE more favorably catalyze butyrylcholine (BCh) but can also
hydrolyzes ACh up to some extent [8,9]. On the basis of cholinergic hypothesis, memory impairment in
the patients of Alzheimer’s disease (AD) and dementia is due to selective and irreversible insufficiency in
the cholinergic functions in the brain [10]. Dementia, rottenly also called senility, is a vast group of brain
diseases that often cause long term and gradual decline in thinking ability of the person. It is great enough
for affecting a person’s daily life functions [11]. Other most common syndrome includes problem with
language, emotional problem and a decrease in motivation [12]. Usually, a person’s consciousness is not
affected in dementia [13]. There are different types of dementia, most common is Alzheimer’s disease
which is responsible for 50-60 % cases of dementia are noticed in the adults of USA and Europe. Other
common types include vascular dementia (25%), Lewy body dementia (15%) and frontotemporal
dementia. Less common types include Parkinson’s disease, syphilis, normal pressure hydrocephalus and
Creutzfeldt-Jakob disease. In DSM-5, dementia was reclassified on the basis of various degree of severity
as a neurocognitive disorder[14].
According to WHO report 2001, the number of dementia especially, AD cases in western countries will
be doubled by every twenty years and will become tripled in China and India with twenty nine million
peoples in 2020, mostly owed to increased human longevity [15]. Even though the unknown morphology
of AD, levitation of ACh amount through the inhibition of AChE has been accepted as the most potent
treatment scheme against AD [16]. Therefore, AChE and BChE inhibitors have become the curious
option in the treatment of AD patients. However, existent drugs (donepezil, tacrin and rivastigmine)
having AChE inhibitory are only convincing against the mild type of AD while there is no drug available
that shows BChE activity to present, yet [17]. Consequently, a lot of pressure develop on researchers to

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discover new drugs in order to conflict dementia and AD. Our group selected a series of chalcones
derivatives to test the inhibitory activity of Cholinesterases because chalcones (natural and synthetic)
illustrate a lot of biological activities like anti-fungal [18], anti-tuberculosis [19], analgesic [20], anti-
oxidant [21], anti-leishmanial [22], anti-malarial [23], anti-viral [24,25], anti-inflammatory and
molluscicidal [22], anti-amoebic [26], anti-depressant, anti-convulsant properties [27], and monoamine
oxidase inhibitory (MAO) activity [28] etc. Keeping in-mind the aforementioned biological importance of
chalcones derivatives, herein we explored a series of chalcones based pyrazoline derivatives as potent
cholinesterase inhibitors along with their molecular docking, ADME properties and established SAR.
2. Materials and methods
2.1. Synthesis of chalcones derivatives
A systematic scheme for the synthesis of piperidyl-thienyl chalcones (1a-1j) and 2-pyrazoline derivatives
of quinolyl thienyl chalcones (2a-2ab) has been already published in our previous papers [29,30].
2.2. Materials
All the chemicals and reagents including Electric eel AChE, quine serum BChE, acetythiocholine
chloride, butyrylthiocholine chloride, 5,5′-Dithiobis[2-nitrobenzoic acid]] (DTNB) were purchased from
Sigma Aldrich (St. Louis, MO, USA) and Merck (Darmstadt, Germany). All chemicals used were of
analytical grade. Neostigmine and donepezil were used as standard drugs.
2.3. Cholinesterases (AChE and BChE) assay protocol
The cholinesterases (AChE& BChE) inhibition studies were determined by Ellmann’s spectrophotometric
method [31] with slight modifications using acetylthiocholine chloride and butyrylthiocholine chloride as
substrates for AChE & BChE, respectively. Total reaction mixture was 100 µL that contain 60 µL
phosphate buffer (50 mM, pH 7.7), 10 µL test compound (1% DMSO, final conc. of compound 0.1 mM
well-1) and 10 µL of AChE (0.015U/well, E.C.3.1.1.7, from electric eel) or 10
E.C.3.1.1.8, from equine serum). The contents of each well was mixed thoroughly followed by incubation
at 37 °C for 10 min and their absorbance was recorded at 405 nm as optical density. Then, 10
L substrate
(0.5 mM acetylthiocholine chloride) for AChE inhibition assay or (0.5 mM butyrylthiocholine chloride)
for BChE inhibition assay was added followed by addition of 10
L DTNB (0.5 mM well-1). Then the
µL of BChE (0.01U/well,
µ
µ
mixture was further incubated at 37 °C for 20 min. Finally, absorbance at 405 nm was recorded using 96-
well plate reader (BioTek ELx800, Instruments, Inc. USA). All experiments were performed in triplicate
with their respective control. Neostigmine (0.1 mM well-1) was used as positive control. Percent
inhibition was calculated by using the following formula
% inhibition = 100-(At/Ac) x100

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Where “At” and “Ac” are absorbance obtained for respective enzyme (AChE & BChE) in the presence
and absence of the inhibitors, after subtracting the respective background (pre read absorbance)
2.4. Molecular docking studies
Molecular docking studies of most potent compounds in both series were carried out against AChE using
MOE [32]. Prior to docking of potent compounds inside the target enzyme, structure were drawn and
protonated in the molecules sketcher tool of MOE. The required protonated 3D structures of these
compounds were obtained using the three-dimensional tool of MOE. Subsequently, the energy
minimization of generated molecules was carried out using the MMFF94x force field with the adjustment
of hydrogen. Finally, the created database was used as input file for docking studies in MOE. For docking
purpose X-ray structure of AChE (PDB ID 1EVE) was selected as template and downloaded from RSC
Protein Data Bank [33]. Prior to docking process protonation of target structure was accomplished using
MOE protonate 3D tools which was followed by energy minimization up to 0.05 Gradient using Amber99
force field. Prior to molecular docking, active site of receptor was selected around the co-crystallized
ligands. Then the required ligands were docked into the active site of protein using Triangular Matching
docking method and 30 conformations of each Ligand protein complex were generated with docking
score. Each complex was analyzed for interactions and their respective 3D pose was visualized using
discovery studio visualizer v4 [34]. Binding free energies were determined and tabulated in table 3. Those
poses having lowest free binding energy values were considered as the most stable-one and selected for
visualization of binding interactions with the target enzyme.
3. Results and discussions
3.1. Chemistry
4-(Piperidin-l-yl) benzaldehyde was prepared by N-arylation of piperidine with 4-flurobenzaldehyde in
the presence of cetyltrimethylammonium bromide (CTAB) as catalyst. It was then condensed with wide
range of different substituted acetylthiophenenes and acetylfurans for getting respective chalcones,
scheme A [30]. Another Chalcones based quinolone series was prepared by reacting it with substituted 2-
chloro-3-formylquinolines and was further reacted with hydrazine hydrate to get 2-pyrazoline derivatives,
scheme B [29]. All these newly synthesized compounds were characterized by different analytical
techniques. The relevant spectroscopic data and physicochemical properties of all these compounds (1a-
1j and 2a-2ab) have been already reported previously [29,30]

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Scheme A. systematic layout for the synthesis of piperidyl chalcones [29]
Scheme B. systematic layout for the synthesis of 2-pyrazoline derivatives of chalcones [30]
3.2. In vitro cholinesterases inhibition studies
A series of piperdyl-thienyl and 2-pyrazoline derivatives of quinolyl-thienyl chalcones were screened
against cholinesterases (AChE and BChE). For both enzymes, all compounds were initially tested at 100
µM concentration and their % inhibition was calculated. Compounds having > 50% inhibition were
further diluted and tested at eight different concentrations to create dose response curves from which their
IC50 values were calculated. Neostigmine and donepezil were used as standard inhibitors for both
enzymes (Table 1-2).
3.2.1. Structure- activity relationships (SAR)
Screening of piperidyl-thienyl chalcones derivatives (1a-1j) against cholinesterases (AChE & BChE)
revealed that all these compounds exhibited good inhibitory potential against acetylcholinesterase while
exhibited relatively less inhibitory potential against butyrylcholinesterase enzyme (Table 1). Experimental
results showed that compounds with no halogen or methyl group attached to thiophene-2-yl or thiophene-
3-yl, (1a&1b) showed relatively low activity against AChE inhibition. While addition of halogen/methyl

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group at thiophene ring increased the inhibition potency up to several folds. However, when tested on
AChE, compounds having 3-chlorothiophen-2-yl, (1e) and 3-bromothiophen-2-yl (1h) moiety at
piperidene chalcones, were found to be the most potent inhibitors having IC50 values 0.16±0.008 µM and
0.19±0.009 µM, respectively. These compounds exhibited up to 142 and 120 fold higher inhibitory
potential as compared to the reference inhibitor, Neostigmine (IC50 ± SEM= 22.2± 3.2 µM). Higher
inhibitory potency of 1e and 1h might be due to the presence of electron withdrawing group, chlorine and
bromine, respectively at 3-position of thiophene ring. On the other side, substituting the same group at 5-
position decreased their inhibitory potency (1f & 1i). Di-substitution in thiophine ring (1g) with chlorine
at position 3 and 5 exhibited no significant change in inhibitory activity due to their cancellation effects
while, inhibition potential seemed to be increased when methyl group was attached at 4-position in
thiophene ring (1c) as compared to the attachment of methyl group at 5-position (1d). Against BChE,
compound having 5-iodiothiophen-2-yl moiety at piperidene chalcones (1j), was found to be the most
potent inhibitor with 46.9% inhibition. It may be due to the presence of iodo-group.
Similar to piperidyl-thienyl derivatives, screening of 2-pyrazoline derivatives of chalcone compounds
(2a-2ab) for the inhibition of AChE & BChE revealed, that all these compounds showed promising
inhibitory potential against acetylcholinesterase. The behavior of the 2-pyrazoline derivatives for different
groups attached at thiophene ring almost remained same as it was seen in piperidyl-thienyl derivatives.
Out of all investigated compounds, compound 2m, 2y and 2w exhibited most potent inhibitory potential
against AChE with an IC50 of 0.13±0.006, 0.15±0.008 and 0.20±0.009 µM, respectively. It has been
noticed that by changing position of different substituents at quinolone ring also potentially effect the
inhibitory activities. From comparative analysis of inhibitory potential of compounds 2h, 2p and 2n,
revealed that compound 2p exhibited high inhibitory activity while compound 2n showed less inhibitory
activities. All of the three compounds have 5-Cl at thiophene ring while 2h contained 6-methyl, 2p had 8-
methyl and 2n had 7-methyl, respectively at 2-pyrazoline ring. All the 2-pyrazoline derivatives showed
relatively less (<50%) inhibitory potential against butyrylcholinesterase (Table 2).
3.2.2. Kinetic study
Kinetic studies of potent compounds 1e and 2m were performed to investigate the mechanism of
inhibition. Based on the obtained data, compound 1e inhibit the enzyme competitively (Fig. 1), while
compound 2m showed mix type of inhibition (Fig. 2). Briefly, the initial velocities of the reactions were
measured at different concentrations of inhibitors (0.05-0.2 µM) and substrate acetylthiocholine chloride
concentrations (0.25-1.5 mM). A double reciprocal plot of the inhibition kinetics of AChE by inhibitors
1e was measured by using PRISM 5.0 (Graphpad, San Diego, California,USA). Results showed that value
of Vmax remained almost same in the presence or absence of inhibitor, represent a competitive type of
inhibitory mechanism. Similarly, Linweaver-Burk double reciprocal plot for 2m was also generated (Fig.

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2). The interception of the lines in the Lineweaver-Burk plot above the x-axis with both increased slope
and intercepts at increasing concentrations of the inhibitor proved a mixed type of inhibition. Compound
2k might be capable to interact with both the catalytic active site (CAS) and peripheral anionic site (PAS)
of acetylcholinesterase.
3.3. Molecular docking
Molecular docking studies of all tested compounds were carried out to calculate the free binding energy
using MOE (Tab. 3). To identify the plausible binding modes, detailed molecular docking analysis of
potent compounds in both series against AChE were also performed. The binding orientation of potent
compounds 1e, 2m and co-crystal ligand within active site of target enzyme is shown in (fig.3). The
putative binding mode of 1e (most potent inhibitor in piperidyl chalcone series) and 2m (most potent
inhibitor in 2-pyrazoline chalcone series) within active site of AChE (fig.4). Analyzing the key
interactions of both 1e and 2m in active site of AChE revealed that both ligands were surrounded by
aromatic ring containing amino acid residue that was Tyr70, Asp72, Trp84, Tyr279, Phe330, Try334 and
His440 (Fig. 4). Further analysis of docking results showed that both ligands are stacked well in the grove
between Trp279 and Trp84 amino acid residues. Both potent compounds had orientation along the active-
site gorge just like reference compound donepezil, extending from active site amino acid residue Trp84,
to the peripheral site amino acid residue Trp279 (Fig. 3). Piperidine ring in compound 1e formed only one
π–
π
stacking interaction with the six-membered ring of the amino acid residue Phe330, contrary to the
interaction of compound 2m in which 2,3-dihydropyridine moiety formed two stacking interaction
with Trp84 and Phe330. Benzene ring adjacent to piperidine ring in compound 1e formed two T-
π–π
π–π
shaped interaction with amino acid residue Tyr121 and Phe331. Carbonyl group adjacent to pyrazole ring
in compound 1e formed two hydrogen bond with Phe288 and Arg289, while NH group of pyrazole ring
in 2m formed hydrogen bond with Asp72. Thiophene ring in both potent compounds formed
π–π
interaction with Trp29.
3.3.1. ADME profile of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones
To evaluate the drug like properties of all investigated molecules, a series of computational filters,
including filters for clogP and predicted solubility were used to select the right compounds from their
library. In general, compounds adhered to Lipinski’s rules 5 (i.e., molecular mass <500, H-bond donors
<5, H-bond acceptors <10, and logP < 5) were proceed for their catalytic potentials. In-silico evaluation
of ADME profile for all these compounds were done along with calculation of free binding energies and
other different ADME properties. The targeted properties, i.e., logP(o/w) (octanol-water partition
coefficient), HBDH (number of hydrogen bond donor atom), HBAH, (number of hydrogen bond acceptor
atom and TPSA (topological polar surface area) were successfully evaluated (Table 3). Among all these
38 tested compounds only 9 compounds 1a, 1b, 1c, 1d, 2a, 2b, 2i, 2l and 2u has logP < 5, which is a

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measure of lipophilicity, while all the remaining compounds have logP > 5. Similarly, other ADME
properties of all tested compounds are rightly in an agreement with the Lipinski’s rules 5. On the other
side most important aspect of these compounds are TPSA values which often used as a model for
assessment of ability of molecules to cross the blood–brain (BBB) was < 40, indicating its potential to
reach brain quickly, bypassing the BBB cut off filter TPSA < 60.
Conflict of interest
The authors confirm that this article content has no conflict of interest.
Acknowledgements
Jamshed Iqbal is thankful to the Organization for the Prohibition of Chemical Weapons (OPCW), The
Hague, The Netherlands and Higher Education Commission of Pakistan for the financial support through
Project No. 20-3733/NRPU/R&D/ 14/520.
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Figures Legends
Fig.1. Double reciprocal plot of the inhibition kinetics of AChE by compound 1e, indication of
competitive inhibition.
Fig.2. Double reciprocal plot of the inhibition kinetics of AChE by compound 2m, indication of mixed
type inhibition (competitive & noncompetitive).
Fig. 3. Binding orientation of compound 1e, 2m and co-crystalized ligand within active site of target
enzyme
Fig. 4. Putative binding mode of compound 1e (left sided in blue colored) and 2m compound (most
potent inhibitor right side, pink colored) in active site of AChE (green colored)
Tables Legends
Table1. Cholinesterases (AChE & BChE) inhibitory activity of piperidyl- thienyl chalcones
Table 2. Cholinesterases (AChE & BChE) inhibitory activity of 2-pyrazoline derivatives of chalcones
Table 3. Free binding energy and ADME profile of all tested compounds

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Table 1.
Compound
Code
A--
Thiophene-R
Acetylcholinesterase
IC50 ± SEM (µM)
2.92 ±0.12
Butyrylcholinesterase
% inhibition
25.6
1a
1b
2.20 ±0.10
1.29±0.06
38.5
29.4
1c
1.59±0.07
15.0
39.4
1d
1e
0.16±0.008
1.70±0.07
43.7
1f

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0.26±0.01
19.0
30.9
1g
1h
0.19±0.009
0.40±0.02
1.31±0.06
19.7
46.9
1i
1j

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Table 2.
Compound
Code
B---R
Acetylcholinesterase
IC50 ± SEM (µM)
Butyrylcholinesterase
% inhibition
C---R
D---R
2.79±0.12
0.86±0.04
20.3
41.1
2a
2b
0.67±0.05
0.79±0.05
29.4
25.0
2c
2d
0.95±0.05
1.20±0.06
0.48±0.02
39.1
26.7
29.0
2e
2f
2g

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0.75 ±0.04
0.99±0.05
33.4
39.7
2h
2i
0.96±0.05
1.01 ±0.05
1.50±0.07
21.9
25.5
28.5
2j
2k
2l
0.13±0.006
0.94±0.04
29.4
25.0
2m
2n
1.60±0.06
39.4
2o
0.29 ±0.02
1.50±0.06
32.7
29.0
2p
2q
2.80±0.13
2.40±0.12
37.9
29.7
2r
2s

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1.20±0.12
41.4
20.4
2t
0.34±0.02
2u
3.80±0.18
25.0
29.4
2v
0.20±0.009
2w
2.80±0.13
40.7
28.9
2x
2y
0.15±0.008
3.82±0.18
40.9
2z
0.40±0.03
0.90±0.06
29.7
42.9
2aa
2ab
Positive
control
-
Neostigmine
22.2 ± 3.2

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Table 3.
Compound Free binding
logP
M. wt
HBAH
HBDH
TPSA
Code
Energy
-12.7258
-12.8723
-12.2148
-12.5155
-13.2676
-12.3297
-13.0677
-13.2028
-12.2910
-11.9044
-12.6916
-13.6930
-14.6531
-12.4782
-13.6872
-13.6625
-13.7014
-13.5584
-13.4378
-12.6852
-12.4904
-12.9312
-13.7514
-13.7103
-12.5622
-13.5187
-13.4250
-13.5699
-13.1794
-13.3148
-13.7570
-13.2814
-14.6108
-13.1510
-14.6335
-13.7570
-13.4612
-13.1807
4.484
4.484
4.818
4.661
5.074
5.288
6.248
5.280
5.494
5.886
4.183
4.516
6.511
6.223
5.831
5.617
5.625
5.411
4.902
5.078
5.116
4.959
5.292
5.372
5.586
6.546
5.578
5.792
5.117
5.155
4.998
5.411
5.625
6.585
5.155
5.831
6.223
1.311
297.422
297.422
311.449
311.449
331.867
331.867
366.312
376.318
376.318
423.318
325.799
339.826
371.871
453.735
406.735
406.735
362.284
362.284
327.839
341.866
341.866
341.866
355.893
362.284
362.284
396.729
406.735
406.735
341.866
341.866
341.866
362.284
362.284
396.729
341.866
406.735
453.735
223.296
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
20.31
20.31
20.31
20.31
20.31
20.31
20.31
20.31
20.31
20.31
50.42
50.42
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
37.28
29.54
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
2y
2z
2aa
2ab

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Fig. 1.
Fig. 2.

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Fig. 3.
Fig. 4.