In Silico Prediction and Molecular Docking Studies of N-Amidoalkylated Derivatives of 1,3,4-Oxadiazole as COX-1 and COX-2 Potential Inhibitors

 

Pavlo V. Zadorozhnii*, Vadym V. Kiselev, Nataliia O. Teslenko, Aleksandr V. Kharchenko,

Ihor O. Pokotylo, Oxana V. Okhtina, Oxana V. Kryshchyk

Department of Organic Substances and Pharmaceutical Preparations, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine.

 

ABSTRACT:

In this paper, using the PASS and GUSAR software packages, we have prognosed the analgesic activity and acute toxicity of N-amidoalkylated derivatives of 2-amino-5-aryl-1,3,4-oxadiazole. Presumably, the analgesic activity of these compounds is associated with inhibition of the COX-1 and COX-2 enzymes. Therefore, in silico inhibition modeling of these enzymes has been carried out, using the ArgusLab 4.0.1 software package.  The studied structures are shown to preferentially form stronger complexes with enzymes, in comparison with known inhibitors. The compounds hits have been selected, based on the results of molecular docking.

 

 

 

INTRODUCTION:

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world¹. Their ability to relieve symptoms of inflammation and pain is usually due to inhibition of cyclooxygenases (COX), the enzymes involved in the synthesis of prostanoids^2,3. COX-1^4,5 and COX-2⁶ enzyme isoforms are of greatest interest as biological targets for NSAIDs. COX-1 is a constitutive enzyme, that is, it works almost constantly and performs physiologically important functions⁷, while COX-2 is an inducible enzyme, that is, it begins to function in certain situations⁷.

 

The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors⁸.

 

Therefore, the search for new COX inhibitors, which along with their effectiveness will have a minimal side effect, is a very important and urgent task. Work on finding potential NSAIDs among substances of natural origin⁹, as well as synthetic derivatives of azepine¹⁰, benzimidazole¹¹, 1,3,4-triazole^12,13, xanthone¹⁴,                    6-nitrocoumarine¹⁵, quinazoline¹⁶, pyrrolidinone¹⁷, pyrrolizine¹⁸, pyrazolone¹⁹, benzothieno[3,2-d] pyrimidine²⁰ and other cyclic and acyclic systems^21,22 is carried out.

 

The derivatives of 1,3,4-oxadiazole²³ have become increasingly interesting as potential COX inhibitors recently. They usually exhibit anti-inflammatory and analgesic activity in vivo in albino rats^24-28 or albino mice²⁹, giving good results in studies in silico^25,27. In this paper, we proposed N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole (1) and (2) as potential inhibitors of COX enzymes (Fig. 1). The search for compounds leaders was based on the results of molecular docking^30,31. The structures for the prediction were taken from our own collection of compounds, obtained by the techniques described in^32,33.

 

Fig. 1: Structures of N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole (1) and (2)

 

 

 

MATERIAL AND METHODS:

In silico prediction of analgesic activity:

Using the PASS system, we analyzed the spectrum of biological activity of N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole (1) and (2). The prediction was obtained for individual structures taken from our own collection of compounds. The structures to be predicted were introduced on the official website (http://www.pharmaexpert.ru) using the graphical editor Marvin Sketch. After that, these structures were sent to the server in the form of MNA-descriptors (Multilevel Neighborhoods of Atoms)^34,35. The results of the prediction of the biological activity spectrum were visualized on the display and saved by "copy-paste". The PASS program predicts the biological activity spectrum of organic compounds, based on their structural formulas, i.e. the biological activity of a substance is considered as its internal property, which depends only on its structure.

 

The PASS system estimates the "similarity/difference" of the test compound with respect to known biologically active substances. The results of the prediction are presented as a list of possible types of activity with estimates of the presence (P_a) and lack of activity (P_i), which have a value from 0 to 1. The greater the value (P_a) and the lower the value (P_i) for a particular activity, the greater the probability of this activity detection under experimental conditions^34,35.

 

In silico prediction of acute toxicity:

The acute toxicity of the studied compounds was evaluated for oral and intravenous routes of administration in rats using the GUSAR³⁶ program (http://www.pharmaexpert.ru). All studied structures of compounds (1) and (2) lie within the QSAR model. To predict the acute toxicity in the GUSAR program, the same algorithm of actions was used as in the prediction of the biological activity spectrum in the PASS program.

 

Ligand Preparation:

The structures of all studied compounds (1) and (2) were optimized within the semi empirical method PM3^37-40 using the ArgusLab 4.0.1⁴¹ software package prior to molecular docking.

 

Proteins Preparation:

Three-dimensional crystalline structures of co-crystallizate of COX-1 enzyme and Ibuprofen (PDB ID: 1EQG)⁴², as well as co-crystallizate of COX-2 enzyme and the inhibitor (S58) 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzenesulfonamide (PDB ID: 1CX2)⁴³ were loaded in the PDB format from the protein molecule data bank (http://www.rcsb.org). Before docking, the molecules of all non-protein components were removed, with the exception of these inhibitors and hemes. The molecules of crystalline water were also removed from the binding site.

 

Molecular Docking Procedure:

Based on the Ibuprofen molecule (COX-1 enzyme), the code in the co-crystallizate 701 IBP, and the molecules of the 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (S58) (COX-2 enzyme), the code in the co-crystallizate 2249 S58, the ligand groups were created named Ligand_X-ray. Based on these groups, three-dimensional models of binding sites were created, their dimensions calculated automatically and made up for COX-1 enzyme along the X axis - 17.098000, the Y axis - 14.533000 and the Z axis - 18.345000 Å and for the COX-2 enzyme - X-23.613000, Y - 19.421000 and the Z axis - 23.120000 Å, respectively.

 

RESULTS AND DISCUSSION:

Prediction of analgesic activity and acute toxicity:

All tested compounds (1) and (2) are likely to exhibit analgesic (38.4-69.3%) activity (Table 1), and have relatively little toxicity. The maximum calculated toxicity value for the intravenous route of administration (IV) corresponds to compound (2a) (LD₅₀ is 103.6 mg/kg), and for the oral route of administration (Oral.) - to compound (2g) (LD₅₀ is 954.7 mg/kg). While the mean LD₅₀ for compounds (1) and (2) is 175.8 mg/kg and 1748.3 mg/kg for the intravenous and oral route of administration, respectively. That is, the averaged toxicity value for compounds (1) and (2) is slightly higher than, for example, for Ibuprofen, LD₅₀ being 224.100 mg/kg (IV) and 1082.000 mg/kg (Oral.).

 

 

 

 

 

Table 1: The results of prediction of analgesic activity and acute toxicity of N-amidoalkylated derivatives of 1,3,4-oxadiazole (1) and (2).

 

Compound	R	R1	Ar	Analgesic activity		Toxic, LD50 mg/kg
				Pa	Pi	IV	Oral.
1a	C6H5	H	C6H5	0.637	0.015	224.100	1566.000
1b	C6H5	H	4-CH3C6H4	0.597	0.020	229.600	2386.000
1c	C6H5	H	4-CH3OC6H4	0.519	0.033	174.400	1684.000
1d	C6H5	H	3-Br-C6H4	0.505	0.036	329.500	1709.000
1e	C6H5	H	4-C5H4N1)	0.589	0.021	181.900	1364.000
2a	CH3	CCl3	4-CH3C6H4	0.693	0.010	103.600	1586.000
2b	C6H5	CCl3	C6H5	0.620	0.017	159.500	1895.000
2c	C6H5	CCl3	4-CH3C6H4	0.583	0.022	142.800	2325.000
2d	4-CH3C6H4	CCl3	C6H5	0.583	0.022	142.800	2325.000
2e	4-CH3C6H4	CCl3	4-CH3C6H4	0.589	0.021	144.500	1809.000
2f	4-CH3C6H4	CCl3	2-NO2-C6H4	0.388	0.078	141.300	1614.000
2g	4-CH3C6H4	CCl3	4-NO2-C6H4	0.384	0.080	167.500	954.700
2h	2,4-ClClC6H3	CCl3	4-CH3C6H4	0.614	0.018	144.200	1510.000

*4-C₅H₄N – pyridyl.

 

Molecular Docking Results for Etalons:

The manifestation of analgesic activity by substances of non-opioid nature is usually associated with COX-1 and COX-2 inhibition. When carrying out molecular docking with COX-1 as a reference, we used Ibuprofen, its calculated binding energy with the active site of the enzyme being -12.2534 kcal/mol, the calculation time being 5 s. The calculated results of Ibuprofen position in the active site of the enzyme are slightly different from the results obtained by X-ray diffraction analysis (Fig. 2), the root-mean-square deviation of atomic positions (RMSD) being 5.889591 Å. At the same time, the system of intermolecular hydrogen bonds between the molecule of Ibuprofen and the amino acids of the active site of COX-1 is preserved. Thus, according to X-ray analysis⁴², there are three intermolecular hydrogen bonds between the carboxyl group of the Ibuprofen molecule and the amino acids of the active site of COX-1. Two of them (2.910301Å in length, 2.834723 Å) are formed with the participation of the guanidine fragment Arg 120, and one - with the participation of the hydroxyl group Tyr 355 (length 2.782572 Å). But according to the calculated data, there are four intermolecular hydrogen bonds between the carboxyl group of the Ibuprofen molecule and the amino acids of the active site of COX-1. Three of them (length 2.561715 Å, 2.842134 Å, 2.977358 Å) are formed with the participation of the guanidine fragment Arg 120, and one - with the participation of the hydroxyl group Tyr 355 (length 2.150595 Å).

 

 

a)

 

 

b)

Fig. 2: The position of the Ibuprofen molecule in the active site of COX-1 enzyme, according to X-ray diffraction analysis (a)⁴² and molecular docking (b), the energy of the complex is -12.2534 kcal/mol. RMSD is 5.889591 Å. Visualization in PyMOL⁴⁴. A heme is depicted in blue tones in the background.

 

We chose 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (S58) as a reference among COX-2 inhibitors, the calculated binding energy with the active site of the enzyme being -9.44774 kcal/mol, the calculation time - 8 s. The calculated results of the inhibitor position (S58) in the active site of the enzyme are close to those obtained by X-ray diffraction analysis (Fig. 3), RMSD is 3.074501 Å. The calculated system of intermolecular hydrogen bonds between (S58) and the amino acids of the active site of COX-2 is somewhat different from the experimental one. Thus, according to the X-ray diffraction analysis, there are three intermolecular hydrogen bonds between 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide molecule (S58) and the amino acids of the active COX-2 site formed by one atom of the Oxygen sulfonamide fragment and the amino acids Gln 1294, Ser 1455 and Leu 1454, while the second atom of the Oxygen sulfonamide fragment does not participate in the formation of hydrogen bonds. According to molecular docking data, there are also three intermolecular hydrogen bonds between (S58) and COX-2, but both Oxygen atoms of the sulfide fragment participate in their formation. The first Oxygen atom forms bonds with Ser 1455 and His 1192, and the second - with Arg 1615.

 

 

a)

 

 

b)

Fig. 3: Position of the molecule of the 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (S58) in the active site of COX-2 enzyme according to the X-ray diffraction analysis (a)⁴³ and molecular docking (b), the energy of the complex is -9.44774 kcal/mol. RMSD is 3.074501 Å. Visualization in PyMOL⁴⁴.

 

Molecular Docking Results for COX-1:

According to molecular docking results, the most stable complexes with COX-1 enzyme form compounds (2h), (2d) and (2c). The energy of the complexes with other studied structures is somewhat higher (Table 2). Compounds (1a), (1c), (1e), (2a) (2e-g) are inferior to Ibuprofen in strength of the complex formed with the enzyme.

 

Table 2: The result of molecular docking of N-amidoalkylated derivatives of 1,3,4-oxadiazole with COX-1.

Compound	∆G with COX-1, kcal/mol	Time, s
1a	-11.9288	5
1b	-12.2992	5
1c	-10.8262	5
1d	-12.3704	4
1e	-10.2422	4
2a	-11.3209	4
2b	-13.4122	4
2c	-13.4768	5
2d	-13.7150	5
2e	-11.8421	4
2f	-11.1984	4
2g	-11.3644	4
2h	-13.8948	4

 

The strongest complex with COX-1 forms 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-amino)ethyl)benzamide (2h). Additional stabilization of the ligand in the active site of the enzyme (Fig.4) is due to the presence of two intermolecular hydrogen bonds formed between the amide and the amino groups of the compound (2h) and the hydroxyl group of the tyrosine amino acid Tyr 355. The length of the hydrogen bond NH...OH (Tyr 355) is 2.837777 Å, and the bond C(O)NH...OH (Tyr 355) - 2.695161 Å.

 

 

 

Fig. 4: Position of the 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide molecule (2h) in the active site of COX-1 enzyme, according to molecular docking data, the energy of the complex is -13.8948 kcal/mol. Visualization in PyMOL⁴³.

 

4-Methyl-N-(2,2,2-trichloro-1-((5-phenyl-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide (2d) effectively binds to COX-1 enzyme due to the formation of two intermolecular hydrogen bonds (Fig. 5). Both hydrogen bonds are formed with the participation of two Nitrogen atoms of the pyridine type of the 1,3,4-oxadiazole ring and the hydroxyl group of the serine amino acid Ser 353. The bonds lengths are 2.070171 Å and 2.406366 Å.

 

 

Fig. 5: Position of the 4-methyl-N-(2,2,2-trichloro-1-((5-phenyl-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide (2d) molecule in the active site of COX-1 enzyme, according to molecular docking data, the energy of the complex is -13.7150 kcal/mol. Visualization in PyMOL⁴³.

 

 

N-(2,2,2-Trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)-amino)ethyl)benzamide (2c) does not form hydrogen bonds with the active site of COX-1 enzyme (Fig. 6).

 

 

Fig. 6: Position of the N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide (2c) molecule in the active site of COX-1 enzyme, according to molecular docking data, the energy of the complex is -13.7150 kcal/mol. Visualization in PyMOL⁴³.

 

 

Molecular Docking Results for COX-2:

According to the results of molecular docking, compounds (2h), (2e) and (1d) form the most stable complexes with COX-2 enzyme. The energy of the complexes with other studied structures is somewhat higher (Table 3). All compounds (1a-e) and (2a-h) exceed the inhibitor (S58) in strength of the complex formed with the enzyme.

 

 

Table 3: The result of molecular docking of N-amidoalkylated derivatives of 1,3,4-oxadiazole with COX-2.

Compound	∆G with COX-2, kcal/mol	Time, s
1a	-12.9460	10
1b	-12.8935	11
1c	-11.4045	10
1d	-14.0228	10
1e	-10.7394	9
2a	-11.7216	11
2b	-12.7000	10
2c	-13.5038	11
2d	-12.7299	10
2e	-14.4659	12
2f	-11.5698	11
2g	-10.5921	10
2h	-14.0313	11

 

4-Methyl-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadi-azol-2-yl)amino)ethyl)benzamide forms the strongest complex with COX-2 (2e). Additional stabilization of the ligand in the active site of the enzyme (Fig. 7) is due to the presence of two intermolecular hydrogen bonds formed between the amino group and the Nitrogen atom of the N(3) 1,3,4-oxadiazole ring of the compound (2h) and the hydroxyl group of the tyrosine amino acid (Tyr 1457). The length of the hydrogen bond NH...OH (Tyr 1457) is 2.996843 Å, and the N...HO (Tyr 1457) bond is 2.923738 Å.

 

 

Fig. 7: Position of the 4-methyl-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide (2e) in the active site of COX-2 enzyme, according to molecular docking data. The energy of the complex is -14.4659 kcal/mol. Visualization in PyMOL⁴³.

 

When binding to the active site of the enzyme, 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadi-azol-2-yl)amino)ethyl)benzamide (2h) forms one hydrogen bond (Fig.8) due to the Oxygen atom of the 1,3,4-oxadiazole ring and the hydroxyl group of the tyrosine amino acid Tyr 1457. The bond length is 2.896642 Å.

 

 

Fig. 8: Position of the molecule 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide (2h) in the active site of COX-2 enzyme, according to molecular docking data. The energy of the complex is -14.0313 kcal/mol. Visualization in PyMOL⁴³.

 

N-(((5-(3-Bromophenyl)-1,3,4-oxadiazol-2-yl)amino)-methyl)benzamide (1d) effectively binds to the COX-2 enzyme due to the formation of two intermolecular hydrogen bonds (Fig. 9). Hydrogen bonds are formed by: 1) the Nitrogen atom of the N(3) 1,3,4-oxadiazole ring and the -NH group of the amino acid arginine (Arg 1222), the bond length is 2.948615 Å; 2) the amine fragment of the compound (2h) and the hydroxyl group of the tyrosine amino acid (Tyr 1457), the bond length is 2.999655 Å.

 

 

Fig. 9: Position of the molecule N-(((5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)amino)methyl)benzamide (1d) in the active site of COX-2 enzyme, according to molecular docking data. The energy of the complex is -14.0228 kcal/mol. Visualization in PyMOL⁴³.

 

CONCLUSION:

In this work, using the software packages PASS and GUSAR, we have predicted the analgesic activity and acute toxicity of N-amidoalkylated derivatives of 2-amino-5-aryl-1,3,4-oxadiazole. Presumably, the analgesic activity of these compounds is associated with inhibition of the COX-1 and COX-2 enzymes. Therefore, using the ArgusLab 4.0.1 software package, in silico modeling of the inhibition of these enzymes has been carried out. It is shown that the studied structures preferentially form stronger complexes with enzymes, in comparison with known inhibitors. Compounds hits have been selected based on the results of molecular docking.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 20.08.2017           © RJPT All right reserved

Research J. Pharm. and Tech 2017; 10(11): 3957-3963.