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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5449_Библиотеки_им_академика_М_И_Перельмана
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ture was conducted with the Chem Draw Ultra software, followed by its importation
into MOE. The low model MD method was employed to generate the initial low-
energy conformation, utilizing the MMFF94x force field and Gasteiger-Hückel charges.
Subsequently, 10,000 iterations were conducted with an RMS gradient of 0.01 kcal. To
facilitate the docking calculations, the compounds were entered into the database and
then stored in the form of an MDB file. The resolution of protein structural issues in
the production of the target protein was achieved by the incorporation of polar hy-
drogen atoms and the optimization of the hydrogen bond network. The protein was
subjected to the MMFF94x force field configuration with partial charges. The site
finder module integrated into the MOE program was utilized to identify the inhibitor-
binding pocket. The docking of the ligand into the active site of the protein was per-
formed using the default parameter procedures. Position: aligning triangle, Correc-
tion: inflexible receptor, this study employs the London dG and GBVI/WSA dG scoring
methods, with a maximum of 50 conformations. In order to assess the free energy of
binding of the ligand from a particular pose, a total of 50 docking conformations were
created for each ligand. These conformers were then ranked using the London dG
scoring function. In order to elimina te duplicate conformations, the conformations
were revised and rescored using the same force field. Upon completion of the docking
process, the posture with the lowest score was selected among the total conforma-
tions. Subsequently, the binding orientations were examined in each subsequent
docking process. The ultimate result of the docked postures is denoted by the final
score S, specifically the GBVI/WSA dG score [19].
5.2.1 Molecular docking with human pancreatic alpha-amylase protein
The significance of molecular binding in the field of drug development is widely ac-
knowledged. A molecular docking analysis was conducted on the active sites of the
human pancreatic alpha-amylase protein receptor to identify a ligand that could po-
tentially decrease postprandial hyperglycemia by reducing the rate of dietary starch
breakdown. The findings (Tab. 5.1) derived from this investigation indicate that com-
pounds C-2 and C-3 exhibit a favorable binding affinity (S score) with the alpha-
amylase protein receptor, while compounds C-1 and C-4 demonstrate a moderate
binding affinity compared to acarbose.
The study investigated the interactions between compounds 9 and 12 and the re-
ceptor for pancreatic alpha-amylase protein, as seen in Fig. 5.3. Compound 10 exhib-
ited the highest binding affinity among the four compounds. This can be attributed to
the presence of a single N-(pyrimidin-2-yl)benzenesulfonamide–NH– bond, which cre-
ates an H-donor contact with amino acid His201. Additionally, the phenyl fragment of
compound 10 forms an H-pi interaction with amino acids Leu162 and Thr163. A lim-
ited number of hydrophobic interactions have been observed between pyridine and
phenyl moieties with the Ile235, Ala198, Leu162, Leu165, Trp59 and Ala106 residues.
5.2 Docking protocol 81
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Numerous ionic interactions were observed between compound 10 and polar amino
acids including Glu233, Tyr151, Lys200, His201, Asp300, Gly306, Tyr62, His305, Thr163,
Gly104, Gly164 and Asn105.
5.2.2 Molecular docking with human maltase-glucoamylase protein receptor
The study investigated the interactions between compounds 13 and 14 and the receptor
for pancreatic maltase-glucoamylase protein, as seen in Fig. 5.4. In comparison to com-
pound 14, compound 13 exhibited a reduced binding affinity (S = −7.17 kcal/mol) toward
the human maltase-glucoamylase protein (−6.50 kcal/mol). The ionic interaction between
ligand one's sulfonamide nitrogen atoms and amino acid Lys 1164 has been detected. Mol-
ecule 13 in this complex contains dimethylisoxazolyl-4-methylbenzenesulfonamide at its
opposite end. This molecule forms polar interactions with the acidic and basic amino
acids Asp1157, Asp1526, Asn1527, Arg1510, Asp1420, His1584, Asp1279 and Tyr1251. The hy-
drophobic interactions between the aromatic ring of the benzene at one end of com-
pound 13 and the residues Phe 1560, Trp 1355, Phe 1559 and Trp 1369 are seen. Compound
13 has dimethylisoxazolyl moieties at both ends, which exhibit hydrophobic interactions
with the amino acids Pro 1159, Pro 1160, Trp 1523, Met 1421 and Trp 1418.
Tab. 5.1: Compounds 1–9 and cobalt complexes with molecular docking scores for various proteins.
Complex Binding energy S score
kcal/mol
of ligands
Binding energy S score kcal/mol
of respective cobalt complexes
Docked protein
−6.97 to −7.29 kcal/mol −. Human pancreatic alpha-
amylase
−.
−.
−.
−. kcal/mol −. Human maltase-
glucoamylase
−. kcal/mol −.
−. kcal/mol Positive binding energy (no
binding affinity)
Cyclooxygenase-
−. kcal/mol Positive binding energy (no
binding affinity)
Not done −. FAD-dependent NAD(P)H
oxidase
82 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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Fig. 5.3: Visualizing the docked poses of compound 10 with the active site region of the human pancreatic alpha-amylase protein in both 2D and 3D views.
5.2 Docking protocol 83
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Fig. 5.4: The docked postures of compound 13 with the active site area of the human maltase-glucoamylase protein are depicted in both 2D and 3D views.
84 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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Fig. 5.5: The docked poses of compound 16 with the active site region of the FAD-dependent NAD(P)H oxidase enzyme are captured in both 2D and 3D views.
5.2 Docking protocol 85
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5.2.3 Molecular docking with FAD-dependent NAD(P)H oxidase
Compound 16 exhibits the most favorable docking interaction with the FAD-dependent
NAD(P)H oxidase enzyme, with a binding energy of −6.17 kcal/mol. According to in silico
binding investigations, it has been observed that compound 8, which includes a phenyl
acetic acid fragment, has hydrophobic interactions with the residues Ile 52, Leu 60, Leu
40 and Leu 299. The phenyl acetic acid –COOH functional group forms hydrogen bonds
with the –NH
2
group of the amino acid Lys 53. Compound 16 has two N-(phenylsulfonyl)
acetamide moieties that establish hydrogen bonding interactions with the –NH
2
group
of the amino acid Lys 331. The phenylsulfonyl group exhibits polar interactions with
residues Gly 59, His 10 and Thr 301, while displaying hydrophobic interactions with res-
idues Val 304 and Leu 46. These interactions facilitate the placement of compound 16
within the receptor’s binding site (Fig. 5.5).
5.3 Results of PASS prediction studies of hydroxytriazenes
Compound 1
. . Anti-inflammatory
. . Cl-transporting ATPase inhibitor
. . Phospholipid-translocating ATPase inhibitor
. . NADPH peroxidase inhibitor
. . Phthalate ,-dioxygenase inhibitor
. . Thiosulfate dehydrogenase inhibitor
. . Chloride peroxidase inhibitor
. . Creatininase inhibitor
. . Hydroxylamine oxidase inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Laccase inhibitor
. . Adenomatous polyposis treatment
. . CYPD substrate
. . Nitrate reductase (cytochrome) inhibitor
. . Thiol oxidase inhibitor
.
. Omptin inhibitor
. . Polyporopepsin inhibitor
. . Venombin AB inhibitor
. . Loop diuretic
. . Na
+
-transporting two-sector ATPase inhibitor
. . CYPC substrate
. . Glycerol--phosphate oxidase inhibitor
. . Antineoplastic (pancreatic cancer)
. . CYPA substrate
. . Aminobutyraldehyde dehydrogenase inhibitor
. . Platelet aggregation stimulant
86 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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(continued)
. . -Haloacid dehalogenase inhibitor
. . Tpr proteinase (Porphyromonas gingivalis) inhibitor
. . Aldehyde oxidase inhibitor
. . -Phytase inhibitor
. . Ovulation inhibitor
. . Gamma-guanidinobutyraldehyde dehydrogenase inhibitor
. . Fusarinine-C ornithinesterase inhibitor
. . Endopeptidase So inhibitor
. . Apoptosis agonist
. . Diuretic inhibitor
. . Glycosylphosphatidylinositol phospholipase
D inhibitor
. . Pseudolysin inhibitor
. . -O-(-Coumaroyl)-
D-quinate ʹ-monooxygenase inhibitor
. . Thioredoxin inhibitor
. . Aspulvinonedimethylallyltransferase inhibitor
. . Saluretic
. . Antineoplastic (sarcoma)
. . Caspase stimulant
. . Fragilysin inhibitor
. . Thiopurine S-methyltransferase inhibitor
. . Arylsulfate sulfotransferase inhibitor
. . Myosin ATPase inhibitor
. . CYPA expression inhibitor
. . Fibrolase inhibitor
. . Acrocylindropepsin inhibitor
. . Chymosin inhibitor
. . Saccharopepsin inhibitor
. .
Spermidine dehydrogenase inhibitor
. . CDK/cyclin T inhibitor
. . CYPA substrate
. . Sulfur reductase inhibitor
. . Aspergillopepsin I inhibitor
. . Carboxypeptidase Taq inhibitor
. . Anaphylatoxin receptor antagonist
. . Antiviral (picornavirus)
. . -Hydroxyquinoline -monooxygenase inhibitor
. . Sugar phosphatase inhibitor
. . Complement factor D inhibitor
. . Gingipain K inhibitor
. . Nicotine dehydrogenase inhibitor
. . Diabetic neuropathy treatment
. . Ribulose-phosphate -epimerase inhibitor
. .
CYPC inhibitor
. . Linoleate diol synthase inhibitor
. . Cyclooxygenase inhibitor
. . -Hydroxy--oxoadipate synthase inhibitor
. . Menopausal disorders treatment
5.3 Results of PASS prediction studies of hydroxytriazenes 87
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Compound 2
Compound 3
. . Anti-inflammatory
. . Para-Aminobenzoic acid antagonist
. . Phospholipid-translocating ATPase inhibitor
. . Antiprotozoal (toxoplasma)
. . Antineoplastic (pancreatic cancer)
. . Phthalate ,-dioxygenase inhibitor
. . Immunosuppressant
. . NADPH peroxidase inhibitor
. . Anti-infective
. . Glycosylphosphatidylinositol phospholipase D inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Chloride peroxidase inhibitor
. . (S)--Hydroxynicotine oxidase inhibitor
. . CYPC inhibitor
. .
CDK/cyclin T inhibitor
. . Polyporopepsin inhibitor
. . CYPC inhibitor
. . Omptin inhibitor
. . NAT substrate
. . Antineoplastic (sarcoma)
. . Phthalate ,-dioxygenase inhibitor
. . Para-aminobenzoic acid antagonist
. . Thiosulfate dehydrogenase inhibitor
. . Ulcerative colitis treatment
. . Thiopurine S-methyltransferase inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Endopeptidase So inhibitor
. . Glycosylphosphatidylinositol phospholipase D inhibitor
. . Phospholipid-translocating ATPase inhibitor
. . Chloride peroxidase inhibitor
. . Antiprotozoal (coccidial)
. . Oxidoreductase inhibitor
. . Antiviral (trachoma)
. . Omptin inhibitor
. . CYPC inhibitor
. . Polyporopepsin inhibitor
. . CYPC inhibitor
. . (S)--Hydroxynicotine oxidase inhibitor
. . NADPH peroxidase inhibitor
. . Pseudolysin inhibitor
. . CDK/cyclin T inhibitor
88 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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Compound 4
(continued)
. . Hydroxylamine oxidase inhibitor
. . N-Benzyloxycarbonylglycine hydrolase inhibitor
. . Venombin AB inhibitor
. . Anti-infective
. . Diabetic neuropathy treatment
. . (R)--Hydroxynicotine oxidase inhibitor
. . Linoleate diol synthase inhibitor
. . Thioredoxin inhibitor
. . Gamma-guanidinobutyraldehyde dehydrogenase
inhibitor
. . Cl-transporting ATPase inhibitor
. . Nicotine dehydrogenase inhibitor
. . NAT substrate
. . Fragilysin inhibitor
. . Fibrolase inhibitor
. . APOA expression enhancer
. . CYPA expression inhibitor
. . Botulinum neurotoxin A light chain inhibitor
. . Nitrate reductase (cytochrome) inhibitor
. . Aminobutyraldehyde dehydrogenase inhibitor
. . Anti-inflammatory
. . Diamine N-acetyltransferase inhibitor
. . Anti-infective
. . Polyporopepsin inhibitor
. . Antiprotozoal (toxoplasma)
. . Antineoplastic (pancreatic cancer)
. . Omptin inhibitor
. . Para-aminobenzoic acid antagonist
. . Glutamyl endopeptidase II inhibitor
. . CYPC inhibitor
. . Phospholipid-translocating ATPase inhibitor
. . CDK/cyclin T inhibitor
. . Growth stimulant
. . CYPA substrate
.
. Antiviral (picornavirus)
. . Immunosuppressant
. . NAT substrate
. . Cl-transporting ATPase inhibitor
. . CYPC inhibitor
. . Venombin AB inhibitor
5.3 Results of PASS prediction studies of hydroxytriazenes 89
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Compound 5
Compound 6
Compound 7
. . Anti-inflammatory
. . Endothelin receptor antagonist
. . Endothelin A receptor antagonist
. . Antihypertensive
. . Phospholipid-translocating ATPase inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Antineoplastic (pancreatic cancer)
. . Anti-infective
. . Polyporopepsin inhibitor
. . Para-aminobenzoic acid antagonist
. . Anti-inflammatory
. . Platelet-derived growth factor receptor kinase inhibitor
. . Anti-infective
. . Insulysin inhibitor
. . CYPC inhibitor
. . CYPC substrate
. . ATP-binding cassette A stimulant
. . NAT substrate
. . Phospholipid-translocating ATPase inhibitor
. . Dihydropteroate synthase inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Arylamine N-acetyltransferase substrate
. . Antineoplastic (pancreatic cancer)
. . Para-aminobenzoic acid antagonist
.
. CYPC substrate
. . Omptin inhibitor
. . NADPH peroxidase inhibitor
. . Thiosulfate dehydrogenase inhibitor
. . Cl-transporting ATPase inhibitor
. . Phthalate ,-dioxygenase inhibitor
. . Adenomatous polyposis treatment
. . Phospholipid-translocating ATPase inhibitor
. . Creatininase inhibitor
. . Glutamyl endopeptidase II inhibitor
. . Polyporopepsin inhibitor
90 Chapter 5 Hydroxytriazenes and their cobalt complexes as candidates
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