Molecular Docking Studies of N-5-Aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacet-amidines as Inhibitors of Enoyl-ACP Reductase Mycobacterium tuberculosis

 

Pavlo V. Zadorozhnii*, Vadym V. Kiselev, Anastasia E. Titova, Aleksandr V. Kharchenko,

Ihor O. Pokotylo, Oxana V. Okhtina

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

 

ABSTRACT:

In this paper, we have carried out in silico modeling of inhibition of enzyme Enoyl-ACP reductase (InhA) Mycobacterium tuberculosis N-5-aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacetamidines using the software package ArgusLab 4.0.1. Based on the results of molecular docking we have selected compounds leaders that form more stable complexes with the enzyme as compared to known inhibitors. The studied compounds are a promising class of compounds with potential anti-TB activity, and they can be recommended for further research to treat this disease. The structures of the investigated compounds have been checked for compliance with Lipinski criteria. The prediction of acute toxicity in rats has been carried out in oral and intravenous routes of administration using GUSAR program.

 

 

 

INTRODUCTION:

Azoles are crucial for medicinal chemistry and pharmaceutical industry. They are widely used in agriculture, in the production of polymers, semiconductors and dyes. Among them, particular attention is drawn to compounds containing the 1, 3, 4-oxadiazole ring, known as substances with a wide spectrum of the biological activity^1-6.

 

Mostly they have antimicrobial^7-14, antiviral^15,16, antioxidant^9,17 and antitumor¹⁸ effect. These substances are of particular interest to fight Alzheimer's Disease¹⁹, and as inhibitors of COX-1 and COX-2 enzymes^20-22, which makes them a promising class of compounds with anti-inflammatory and analgesic effect. Recently, systems with 1,3,4-oxadiazole ring have been used as scaffolds for the subsequent synthesis of compounds with antituberculosis activity^23-27. For example, using (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidi ne-3-carboxamide (1), B. Mathew with colleagues designed and then carried out the synthesis of (E)-1-(furan-2-yl)-N-(5-aryl-1, 3, 4-oxadiazol-2-yl) methanimines (2) (Fig. 1), which possess antituberculosis activity²⁸. As a compound leader they suggested (E)-N-(5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)-1-(furan-2-yl) methanimine (2a) (Fig. 1). The mechanism of action of the compounds obtained is presumably connected to inhibition of Enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis²⁸.

 

Fig. 1: Structures of (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1), (E)-1-(furan-2-yl)-N-(5-aryl-1,3,4-oxa-diazol-2-yl)methanimines (2) and compound leader (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methanimine (2a)²⁸

 

In this study we have proposed 2, 2-dichloroacetamidines with 1,3,4-oxadiazole fragment (3) as potential inhibitors of InhA enzyme (Fig. 2). The search of hit-compounds has been based on the results of molecular docking^29,30. The structures for the prediction have been taken from our own collection of compounds prepared according to procedures described in^31,32.

 

Fig. 2: N-5-aryl-1,3,4-oxadiazolo-2,2-dichloroacet-amidines (3a-e)^31,32

 

MATERIAL AND METHODS:

The Software Used:

Optimization of the geometry of the structures being analyzed and molecular docking with InhA enzyme has been carried out using software Argus Lab 4.0.1³³. Previously, this software package was successfully used to solve similar tasks^34-39.

 

Visualization of the results has been obtained using the programs PyMOL⁴⁰ and Chimera⁴¹. Acute toxicity of the compounds being studied in rats in oral and intravenous routes of administration has been evaluated using GUSAR⁴² program (http://www.pharmaexpert.ru). The compounds (3) have been checked for compliance with Lipinski criteria⁴³ using a web resource Molinspiration (http://www.molinspiration.com/cgi-bin/properties).

 

Ligand Preparation:

The structures of all the compounds being studied (3) have been optimized within PM3 Semiempirical Method^44-47 before molecular docking. To the compound (3c) the obtained results have been compared with the data of X-ray analysis published earlier (CCDC 952084, http://www.ccdc.cam.ac.uk)³¹.

 

Protein Preparation:

The three-dimensional crystal structure of InhA enzyme co-crystallizer and (S)-1-cyclohexyl-N-(3, 5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1) (PDB ID: 4TZK) ⁴⁸ has been loaded in PDB format from the Protein Data Bank (http://www.rcsb.org). Except the molecule of the compound (1) (green) there is NAD molecule (red) in the active site of the enzyme (Fig. 3). NAD takes indirect part in the formation of the compound complex (1) with InhA⁴⁸ through hydrogen bond with a water molecule (H₂O 743). Therefore, neither NAD molecule, nor crystal water molecules (blue) have been removed from the binding site before the docking.

 

Fig. 3: The position of the molecule (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1) (green) and NAD molecule (red) in the active site of InhA enzyme Mycobacterium tuberculosis. Visualization in PyMOL⁴⁰.

 

Molecular Docking Procedure:

Based on the molecule of the compound (1) (co-crystallizer code 501 641), a ligand group named Ligand_X-ray has been created. A three-dimensional model of the binding site has been developed on the basis of this group, its dimensions being calculated automatically and making along the X-axis - 24.817000, the Y-axis - 19.766000 and the Z-axis - 21.712000 Å.

 

Acute Toxicity Prediction:

To predict acute toxicity, the compounds of the structures (3a-e) have been entered on the official website (http://www.pharmaexpert.ru) using graphical editor Marvin Sketch. Then they have been sent to the server as MNA-descriptors (Multilevel Neighborhoods of Atoms)⁴⁹. The results of the prediction have been visualized on the display and saved by «copy-paste». For comparison, we have carried out calculations of toxicity (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1), (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methanimine (2a) and isoniazid (INH).

RESULTS AND DISCUSSION:

Geometry Optimization:

During the molecular docking we have used the compound (1) as a reference and (E)-N-(5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)-1-(furan-2-yl) methanimine (2a) - a compound leader according to the research data²⁸. The built-in protein crystal structure has been used for inhibitor docking (1) with InhA enzyme. In the case of the compound (2a) and amidines (3a-e), we have used molecular structures obtained according to the quantum chemical calculations within the semi-empirical method PM3 (Fig. 4). The total energy of the compound (2a) is -70338.0267 kcal / mol, and the compounds (3a-e) range from -103149.3043 to -86282.3134 kcal / mol.

 

(2a) -70338.0267 kcal/mol	(3a) -91146.0618 kcal/mol	(3b) -86282.3134 kcal/mol
(3c) -89734.1568 kcal/mol	(3d) -103142.3005 kcal/mol	(3e) -103149.3043 kcal/mol

Fig. 4: Molecular structures of (E)-N-(5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)-1-(furan-2-yl) methanimine (2a) and N-5-aryl-1, 3, 4-oxadiazolo-2,2-dichloroacetamidines (3a-e) according to the quantum chemical calculations within the semi-empirical method PM3. Visualization in PyMOL⁴⁰.

 

The results of geometry optimization N-5-aryl-1, 3, 4-oxadiazolo-2,2-dichloroacetamidines (3a-e) indicate their structural similarity with the compound (2a) (Fig. 5), and they are in good agreement with the data of X-ray structural analysis carried out earlier for the compound (3c) (Fig. 6). The values of bond lengths (Table 1) and bond angles (Table 2), obtained experimentally³¹ and by calculation, are very close.

 

 

Fig. 5: Comparison of the spatial structure of the molecule (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methan-imine (2a) (green), the compound (3a) (pink) and (3c) (orange). Visualization in PyMOL⁴⁰.

Fig. 6: Molecular structure of (E)-2, 2-dichloro-1-morpholino-N-(5-(p-tolyl)-1, 3, 4-oxadiazol-2-yl)ethan-1-imine (3c): a) according to XRD data³¹; b) according to quantum chemical calculations within the semi-empirical method PM3. Visualization in Chimera⁴¹.

 

Table 1: The lengths of the bonds in the molecule (E)-2,2-dichloro-1-morpholino-N-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)ethan-1-imine (3c) according to X-ray diffraction data³¹ and quantum chemical calculations within the semi-empirical method PM3.

* Software package ArgusLab 4.0.1 gives bond lengths up to the sixth decimal place, but for the convenience of comparison with XRD data, their value has been rounded to the third decimal.

 

Table 2: The value of the bond angles (E)-2,2-dichloro-1-morpholino-N-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)ethan-1-imine (3c) according XRD data³¹ and quantum chemical calculations within the semi-empirical method PM3.

Group of atoms	Angle, deg.
	XRD data	PM3 method*
C(5)-N(1)-C(4)	128.5(4)	124.3
C(4)-N(1)-C(1)	111.3(4)	112.2
C(7)-N(3)-N(4)	106.6(4)	107.7
C(2)-O(1)-C(3)	108.8(4)	112.7
N(1)-C(1)-C(2)	109.3(4)	110.3
O(1)-C(3)-C(4)	112.7(4)	112.1
N(2)-C(5)-N(1)	118.8(4)	113.3
N(1)-C(5)-C(6)	118.7(5)	122.0
C(5)-C(6)-Cl(1)	112.4(3)	110.6
N(3)-C(7)-N(2)	134.4(5)	135.5
N(2)-C(7)-O(2)	113.7(4)	115.3
N(4)-C(8)-C(9)	128.8(5)	129.8
C(14)-C(9)-C(10)	117.6(5)	119.7
C(10)-C(9)-C(8)	120.5(5)	118.8
C(12)-C(11)-C(10)	121.8(6)	120.5
C(13)-C(12)-C(15)	121.6(6)	121.1
C(12)-C(13)-C(14)	121.5(5)	120.5
C(5)-N(1)-C(1)	119.7(4)	123.5
C(5)-N(2)-C(7)	122.3(4)	125.2
C(8)-N(4)-N(3)	106.4(4)	108.9
C(8)-O(2)-C(7)	103.2(4)	105.7
O(1)-C(2)-C(1)	112.6(5)	112.8
N(1)-C(4)-C(3)	110.2(4)	110.2
N(2)-C(5)-C(6)	122.5(5)	124.7
C(5)-C(6)-Cl(2)	111.8(3)	110.5
Cl(2)-C(6)-Cl(1)	112.8(2)	107.6
C(12)-C(13)-C(14)	121.5(5)	120.5
N(3)-C(7)-O(2)	111.6(4)	109.2
N(4)-C(8)-O(2)	112.2(5)	108.5
O(2)-C(8)-C(9)	119.0(5)	121.7
C(14)-C(9)-C(8)	121.9(5)	121.5
C(9)-C(10)-C(11)	120.0(6)	120.0
C(13)-C(12)-C(11)	117.7(6)	119.4
C(11)-C(12)-C(15)	120.6(6)	119.5
C(13)-C(14)-C(9)	121.4(5)	119.9

*Software package ArgusLab 4.0.1 gives the values of bond angles to the nearest hundredth, but for the convenience of comparison with XRD data, their value has been rounded to the nearest tenth.

 

Molecular Docking Results for Etalons:

The calculated energy of inhibitor binding (1) to the active site of the enzyme is -10.9453 kcal / mol; the calculation time makes 4 seconds. The calculated results of the inhibitor position in the enzyme active site are close to the results obtained by X-ray diffraction method (Fig. 7), root-mean-square deviation of atomic positions (RMSD) is 2.541947 Å.

 

a)	b)

Fig. 7: The position of (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1) in the active site of InhA enzyme according to XRD data (a)⁴⁸ and molecular docking (b), the complex energy -10.9453 kcal / mol. RMSD is 2.541947 Å. Visualization in PyMOL⁴⁰.

The calculated energy (∆G) of inhibitor binding (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methanimine (2a) to the active site of the enzyme is -9.08205 kcal/ mol, the calculation time makes 3 seconds. The results obtained are very close to the results of the research²⁸, according to which the energy of complex InhA-(2a) is -9.7426 kcal / mol. The molecule of the compound (2a) is further fixed in the active site of InhA enzyme due to the complex system of intermolecular hydrogen bonds with the molecules of crystal water - H₂O 818, H₂O 737 and H₂O 743 (Fig 8).

 

Fig. 8: The position of (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methanimine (2a) in the active site of InhA enzyme according to molecular docking, the complex energy -9.08205 kcal / mol. Visualization in PyMOL⁴⁰.

 

Molecular Docking Results for Amidines (3a-e):

According to the results of molecular docking, the most stable complex with InhA enzyme forms the compound (3a), exceeding both (S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1) and (E)-N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-(furan-2-yl)methanimine (2a) on this parameter. The complexes energy with structures (3b) and (3c) is slightly higher. These compounds are inferior to inhibitor (1), but superior to inhibitor (2a) in strength of the complex with the enzyme (Table 3). The compounds (3d) and (3e) are inferior to etalons.

 

Table 3: The results of molecular docking of N-5-aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacetamidines (3a-e).

 

* The value of the complex energy at the docking with the structure obtained as a result of quantum chemical calculations is given for the compound (3c) (Fig. 6b). In comparison with the structure obtained by X-ray analysis (Fig. 6a), the complex energy is somewhat higher and makes -9.35924 kcal / mol.

(E)-N-Benzyl-2,2-dichloro-N'-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)acetimidamide (3a) is efficiently bound to InhA enzyme due to the formation of two intermolecular hydrogen bonds (Fig. 9). A Hydrogen atom of the crystal water molecule (H₂O 743) and a Nitrogen atom N(3) of 1,3,4-oxadiazole ring take part in the formation of one hydrogen bond, the length H...N being 2.873637 Å. A Hydrogen atom of amidine fragment (BnNH) and an Oxygen atom of peptide bond Pro156-Ala157 form the second hydrogen bond, bond length NH...O₁₅₆=С′₁₅₆ (Pro 156) being 2.834225 Å.

 

Fig. 9: The position of (E)-N-benzyl-2,2-dichloro-N'-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)acetimidamide (3a) in the active site of  InhA enzyme according to the results of molecular docking. Visualization in PyMOL⁴⁰.

 

(E)-2,2-Dichloro-1-morpholino-N-(5-phenyl-1,3,4-oxadiazol-2-yl)ethan-1-imine (3b) when bound to the enzyme active site forms a complex system of intermolecular hydrogen bonds with three molecules of crystal water and an Oxygen atom of morpholine cycle (Fig. 10). Hydrogen bonds are formed by: 1) a Hydrogen atom of water molecule (H₂O 819) and an Oxygen atom of morpholine cycle, the bond length H.O - 3.400024 Å; 2) a Hydrogen atom of water molecule (H₂O 818) and an Oxygen atom of morpholine cycle, the bond length H...O - 2.364742 Å; 3) a Hydrogen atom of water molecule (H₂O 737) and an Oxygen atom of morpholine cycle, the bond length H..O - 2.521765 Å.

 

Fig. 10: The position of (E)-2,2-dichloro-1-morpholino-N-(5-phenyl-1,3,4-oxadiazol-2-yl)ethan-1-imine (3b) in the active site of InhA enzyme according to the results of molecular docking. Visualization in PyMOL⁴⁰.

 

(E)-2,2-Dichloro-1-morpholino-N-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)ethan-1-imine (3с) when bound to the enzyme active site it is formed one hydrogen bond with a Hydrogen atom of the crystal water molecule (H₂O 743) and a Nitrogen atom N(2) of 1,3,4-oxadiazole cycle, the length H...N - 2.896771 Å (Fig. 11).

 

Fig. 11: The position of (E)-2, 2-dichloro-1-morpholino-N-(5-(p-tolyl)-1, 3, 4-oxadiazol-2-yl) ethan-1-imine (3с) in the active site of InhA enzyme according to the results of molecular docking. Visualization in PyMOL⁴⁰.

 

Lipinski criteria:

The studied structures have been checked for compliance with Lipinski criteria using a web resource Molinspiration⁴³. All of the compounds correspond to them (Table 4).

 

Table 4: The test of the compounds (3a-e) for compliance with Lipinski criteria.

Compound	Mr	logP	Rot.Bond	Hdonor	Hacceptor
3a	375.26	4.75	6	1	5
3b	341.20	2.99	4	0	6
3c	355.23	3.44	4	0	6
3d	386.19	2.90	5	0	9
3e	386.19	2.95	5	0	9

 

Acute Toxicity:

Antituberculosis drugs have sufficiently high     toxicity^50,51, so the compounds (3a-e) have been evaluated for the acute toxicity in rats using GUSAR program⁴².  For comparison, we have given the results of toxicity calculations (S)-1-cyclohexyl-N-(3, 5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (1), (E)-N-(5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)-1-(furan-2-yl) methanimine (2a) and isoniazid (INH) (Table 5).

 

Table 5: Calculation of the acute toxicity N-5-aryl-1, 3, 4-oxadiazolo-2,2-dichloroacet-amidines (3a-e) in rats in intravenous and oral routes of administration.

*IV – intravenous route; ** Oral. – Oral route.

 

CONCLUTION:

Using the software package ArgusLab 4.0.1 we have carried out in silico modeling of Enoyl-ACP Reductase (InhA) enzyme Mycobacterium tuberculosis inhibition. We have suggested N-5-aryl-1, 3, 4-oxadiazolo-2, 2-dichloroacetamidines as potential inhibitors. Compounds leaders (E)-N-benzyl-2,2-dichloro-N'-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)acetimidamide (3a), (E)-2,2-dichloro-1-morpholino-N-(5-phenyl-1,3,4-oxadiazol-2-yl)ethan-1-imine (3b) and (E)-2,2-dichloro-1-morpholino-N-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)ethan-1-imine (3с) have been selected based on the results of molecular docking, forming more stable complexes with the enzyme as compared to known inhibitors. The studied compounds are the promising class of compounds with potential anti-TB activity, and they can be recommended for the further study of their pharmacological properties. The structures of all compounds studied correspond to Lipinski criteria. The prediction of acute toxicity in rats has been carried out in oral and intravenous routes of administration using GUSAR program.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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