Abstract:
Tuberculosis is one of the most severe bacterial diseases, and it has been documented that it has established multi-drug resistance, making anti-TB medicines almost untreatable. As a result, novel and optimized anti-TB medications with new targets and mechanisms of action are urgently needed for the effective treatment of MDR-TB, XDR-TB, and TDR-TB infected patients. A drug molecule such as bedaquiline documented to be highly selective and precise in inhibiting the essential ATP synthase enzyme, In the present study, we undertake the design of new derivatives of Bedaquiline with different substitutions at various levels and subjected for the ADME prediction for the appropriate Bedaquiline derivative which accompanied by the computer-aided drug design. Considering the binding energies, the lowest binding energy was found to be -7.17 for bdq5 analogue could help in improving potency of compounds against mycobacterium tuberculosis infection.

Tuberculosis is one of the most important bacterial diseases which are reportedly developed multi-drug resistance [1-2]. In 2015, around 480,000 people reported multidrug resistance worldwide with an additional 100000 TB cases with rifampicin resistance. 9.5% of these cases estimated that they were extensively drug-resistant TB (XDR-TB) (WHO, 2016). These tuberculosis resistant strains of mycobacterium species have been troubling due to the ineffectiveness of traditional antimycobacterial treatment [3-4]. Mycobacterial Fatty acid biosynthesis for cell wall is important and vital for developing the resistance [5]. This problem has been made worse by the recent appearance of fully drug- resistant strains of MTB [6] that are almost untreatable by the currently available anti-TB drugs. Therefore, this made an urgent need of the novel and improved anti-TB drugs that attribute new targets and method of action for the successful treatment of MDR-TB, XDR-TB, and TDR-TB infected patients [7-8].

Recent clinical trials on Bedaquiline shows indicated efficacy and potent bactericidal effect in the treatment of multidrug-resistant and extremely drug-resistant tuberculosis strains accompanied with considerably reduced treatment period [9-11]. Currently, it is used as the last-line antibiotic drug in the combination therapies against multi-resistance and extremely resistant tuberculosis strains in the US, European Union states, along with several other countries [12-14].Bedaquiline mechanism of action was reported to be highly selective and specific in inhibiting the essential ATP synthase enzyme [15-17], which is required for the synthesis of the ATP through rotor ring of the bacterial organism’s in replicating and dormant mycobacterium but not in other prokaryotic and eukaryotic cells.In the present investigation, we undertake the design of new derivatives of Bedaquiline with different substitutions at various levels and subjected for the ADME prediction for the appropriate Bedaquiline derivative which accompanied by the computer-aided drug design. 

Design strategy for the Bedaquiline derivatives:

The improved pharmacokinetic and pharmacodynamic properties of the Bedaquiline is achieved by replacing the dimethylamino, naphthalene groups in several derivatives with the isoindoline, tetrazole, carbazole, benzimidazole, quinazolone, dimethylquinazoline groups were added. All the add-on groups substantially contribute the pharmacokinetic, dynamic properties to Bedaquiline due to the presence of nitrogen-containing heterocyclic compounds.

Fig. 1 Reference compound: Bedaquiline

Derivatives of Bedaquiline:

Figure 2.1

Figure 2.2

Fig. 2: Derivatives of Bedaquiline

Hardware and software

The study was carried out on a Dell latitude with a 2.26 GHz processor, 4 GB RAM and 320 GB hard drive running in a Windows 10.0 operating system with help of the Bioinformatics software, such as AutoDock4.2, Marvin, BIOVIA Discovery studio and online resources were used in this study.

Protein preparation:

The specific protein chosen for the Bedaquiline derivatives is Mycobacterial ATP-synthase

F0 rotor protein 4V1f (PDB) extracted through an X-ray diffraction method with a resolution of 1.70 Å.

Ligand preparation:

The ligand generation starts with generating structure in the 2D format in ChemDraw then conversion into the 3D format in PRODRG server and adds the polar hydrogens to the ligand save din the .pdb format for the computational analysis [18].

Protein-ligand docking

Protein-ligand docking studies were performed with one of the most widely used docking program AutoDock4.2 [19-20]. Which is software allowing the in-silico analysis [21-22] of the causative protein with the imaginary structural component to predict the efficiency of the corresponded structural complex by showing the results of the binding capacity of the ligand with the protein complex in a very efficient and economical way.

Visualization:

The visualization was done using the graphical interface of the Auto dock tool and PyMol molecular graphics [23-25].

Binding energies of standard and test compounds:
The docking of the Bedaquiline derivatives with the ATP synthase enzymatic protein for the inhibitory effect efficiency, the compared strategies involved in parent compound and derivatives shows that hydroxyl group at first carbon atom in the acyclic chain is necessary for the inhibitory effect provides high binding capacity with the biological target. Binding energies in the bdq3, bdq4, bdq7, bdq8 shows that dimethyl butan-1amine is doesn’t involved in the binding with the biological target it further proves specific side-chain affect the pharmacokinetic properties of the molecule. the naphthalene substituent with five and six-member heterocyclic with a single nitrogen atom (like in place of naphthalene replaced with indole) shows equal or appropriate binding energy with the parent drug. Adding an extra heterocyclic ring as substituent along with the naphthalene shows decreased in binding capacity of the molecule.
 

Table 1 : binding energies of derivatives.

In silico ADME properties, and another ten pharmacokinetics properties like partition coefficient, aqua solubility, polar surface area, number of rotatable bonds, number of hydrogen bond donors/acceptors, human serum albumin binding, caco-2 cell permeability, blood/brain partition co-efficient and human oral absorption of the 20 compounds were computed by using the PREADMET program. The results of these computations are summarized in Table: which shows that the compounds with saturated heterocyclic rings cross the BBB at a considerable level. In the case of bdq 4 and bdq 10 confirms that plasma protein binding not affected by the acyclic amine side chain in the Bedaquiline derivatives.

Table 2 : pharmacokinetic and dynamic properties of bedaquiline derivatives

Bedaquiline

bdq3

bdq4

bdq5

bdq7

Fig. 3 : Docking interaction between the ligand and protein molecule

Considering the binding energies, it was found that some of were almost near to the binding energies of reference compounds Some of very higher values are found. The lowest binding energy was found to be -7.17 for bdq5 analog and other analogs bdq3, bdq4, bdq7 also shown least binding energy then started. A less variation of around 10% is seen in PPB. When speaking about interactions bdq5 was all the possible interactions like reference compound are LE70, ALA67, ALA66, GLU65, TYR65, PHE69, remaining properties of ADME were almost same as that of reference compound Bedaquiline. In the present work of Docking studies speak for the importance of functional groups of the Bedaquiline and its derivatives, which could help in improving our compounds against mycobacterium infection. This kind of studies we consider as good starting points to improve the design of a novel class of anti-tuberculosis molecules for resistant strains.

All the authors are grateful to Asst. Prof. Dr. K.Naresh , and all the faculty of Department of Pharmaceutical Chemistry, G. Pulla Reddy College of Pharmacy for providing the necessary facilities to carry out this study

All the authors declare that they have no conflict of interest.

All the abbreviations used have been described in the text.