In silico study for evaluating the binding mode and interaction of 1, 2, 4-triazole and its derivatives as potent inhibitors against Lipoate protein B (LipB)

1 Introduction

Tuberculosis still remains a major challenge to mankind caused by Mycobacterium tuberculosis. There are drugs like ethambutol, isoniazid and rifampicin available for curing for tuberculosis. The increasing problem of Multi-Drug Resistant (MDR) tuberculosis has focused the attention of researchers toward the development of novel drugs that are not only shortening the prolonged therapy but also active against disease. (Lamichhane et al., 2011; Maste et al., 2011).

In developing and designing of novel anti-tubercular drugs, it is very important to think about which receptor in the tubercle bacillus is a good drug target. There are many enzymes that partake in the pathogenicity and metabolic process like the growth of the bacterium and one among them is Lipoate biosynthesis protein B (LipB). LipB is an enzyme that participates in lipoylation; it catalyzes the transfer of endogenous octanoic acid to lipoyl domains by forming thioester bond to the 4-phosphopanthetheine cofactor of the acyl carrier protein (ACP). Lipoyl synthase (Lip A) then converts octanoyl derivatives into lipoyl derivatives. Thus it acts as the essential protein involved in activating the bacterium’s metabolic activities (Cade et al., 2010).

Computational approach aids to evaluate the binding affinity and interaction between a ligand and the receptor which help to prioritize drug for screening experimental approach. Protein-ligand docking is a computational method developed to understand the binding mode and interpret the preferred orientation between large molecules (receptor) and small molecule (ligand) in order to form a stable complex. This technique plays a vital role in computer aided drug design (Kitchen et al., 2004). Molecular docking investigations were carried out with the aim of understanding the binding mode and interaction of the 1, 2, 4-triazole derivatives into the active site of LipB of M. tuberculosis.

2 Materials and method

2.2

2.2 Docking procedure

The molecular docking studies were carried between 1, 2, 4-triazole derivatives and M. tuberculosis target site (LipB). The molecular structures 1, 2, 4-triazole derivatives were presented Table 1. These compounds together with their biological activity were obtained from the literature (Sarkar et al., 2016). While the crystal structure of (LipB) was obtained from the Protein Data Bank with code 1W66. All bound substances (ligands and cofactors) and solvent molecules associated with the receptor were removed. Some of the active sites are GLN, ALA, ASP, PHE, CYS, ASN, SER etc. The prepared receptor and ligand were shown in Fig. 1. The prepared ligands were docked with the prepared structure of LipB using Autodock Vina incorporated in Pyrx software. The docked results were then visualized and analyzed using Discovery Studio Visualizer software (Adeniji et al., 2020).

Table 1 Molecular structures of 1, 2, 4-triazole derivatives and their activities.

S/N	Molecule	Activity (% inhibition)
1		03
2		10
3		03
4		11
5		08
6		08
7		01
8		21
9		08
10		85
11		10
12		13
13		86
14		31
15		51
16		98
17		57
18		25
19		94
20		98
21		58
22		25
23		45
24		15
25		89
26		94
27		65
28		22
29		30
30		40
31		88
32		26
33		42
34		98
35		76
36		96
37		88
38		88
39		76
40		96
41		98
42		98
43		98
44		40
45		98
46		98
47		97
48		12
49		09
50		02

Close

Fig. 1

Prepared structure of LipB.

Export to PPT

3 Results and discussion

Molecular docking studies were carried out in order to elucidate the interaction and the binding mode between the target (LipB) and 1, 2, 4-triazole derivatives as potent anti-mycobacterium tuberculosis. The docking results clearly show that the binding affinities of these ligands correlate with their activity values. The binding affinity values for all the compounds range from (−4.1 and 17.9 kcal/mol) as reported in Table 2. Ligands (compound 16 and 34) have higher binding affinities which ranges from (−15.8 to 17.9 kcal/mol) which were greater than the binding affinity of recommended drugs; isoniazid (−14.6 kcal/mol) and ethambutol (−5.8 kcal/mol). Ligands (compound 16 and 34) with best binding affinities were visualized and analyzed using Discovery Studio Visualizer. The 2D and 3D interaction of ligand 16 and 34 as well as recommended anti-tubercular drugs (ethambutol and isoniazid) with LipB target site were shown in Figs. 2 and 3.

Close

Fig. 2

(16a) and (16b) show the 3D and 2D interactions between LipB and Ligand 16. (34a) and (34b) show the 3D and 2D interactions between LipB and Ligand 34.

Export to PPT

Close

Fig. 3

(E_A) and (E_B) show the 3D and 2D interactions between LipB and Ethambutol. (I_A) and (I_B) show the 3D and 2D interactions between LipB and Isoniazid.

Export to PPT

Ligand 16 formed three hydrogen bonds (2.3503, 2.1532 and 2.6856 A) with TYR113 and PRO112 of the target. Hydrophobic interaction is a bond formed between the ligand and the binding pocket of the target site (receptor). It adhere the ligand to the surface of target site as shown in Figs. 4a and 4b. Ligand 16 formed hydrophobic bond with ASP110, PHE109 and ALA111 of the target site. Ligand 34 formed five hydrogen bonds (2.1123, 2.6234, 2.6012, 2.1922 and 2.6302 A) with THR77, GLN385, ALA167, GLN385 and ALA187 of the target while hydrophobic interactions were observed PHE168 and VAL78. The recommended drugs; Isoniazid formed three hydrogen bonds (2.53, 2.25 and 2.30 A) with ALA337, ALA337 and SER273 while hydrophobic bonds were observed with PHE338 and CYS345 while ethambutol formed only one hydrogen bond (2.60°A) with ALA337 with the target site but no hydrophobic interaction which accounts for its low binding affinity.

Close

Fig. 4a

Hydrophobic interaction between the ligand 16 and M. tuberculosis target (LipB).

Export to PPT

Close

Fig. 4b

Hydrophobic interaction between the ligand 34 and M. tuberculosis target (LipB).

Export to PPT

Ligand 16 formed a total of three hydrogen bonds with target site of LipB. The N-H group triazolidine of the ligand acts as hydrogen donor and formed three hydrogen bonds with PHE109, ALA11 and ASP110 of the target. Ligand 34 formed a total of five hydrogen bonds with target site of LipB. The N-H group triazolidine of the ligand also acts as hydrogen donor and formed three hydrogen bonds with GLN385, ALA167, and ALA167 of the target. The S⚌O of the ligand acts as hydrogen acceptor and formed two hydrogen bonds with ASN79 and GLN 385 of the target. The hydrogen bond formation alongside with the hydrophobic interaction provides an evidence that ligand 16 and 34 of the inhibitor compounds are potent against LipB receptor. Elucidations of hydrogen donor and hydrogen acceptor region were shown in Figs. 4c and 4d.

Close

Fig. 4c

H-bond interaction between the ligand 16 and M. tuberculosis target (LipB).

Export to PPT

Close

Fig. 4d

H-bond interaction between the ligand 34 and M. tuberculosis target (LipB).

Export to PPT

4 Conclusion

Analogue of 1, 2, 4-triazole derivatives were evaluated against Mycobacterium tuberculosis target (LipB). The binding affinities of these compounds correlate with their biological activities. Ligands (compound 16 and 34) were found to have the most promising binding affinity values of (−15.8 and 17.9 kcal/mol). In conclusion, this study showed that compound 16 and 34 of 1, 2, 4-triazole derivatives could serve as better anti-tuberculosis drug and need further in vitro investigations to confirm their actual therapeutic potential efficacy and drug ability towards the disease.