Design and Molecular Docking Analysis of Isoniazid-Coupled 5,1H-Tetrazole as Potential Anti-Tubercular Agents Using PyRx and AutoDock (MGLTools-1.5.7)

The World Health Organization (WHO) “Global Tuberculosis Report 2024” underscores the ongoing challenges and progress in the global fight against tuberculosis (TB). Despite a slowdown in the annual increase in TB cases and a decline in TB-related deaths, the disease remains a significant public health threat with 10.8 million new cases reported in 2023. The report reveals a persistently high burden of TB, especially in low- and middle-income countries, and highlights the escalating issue of drug-resistant TB. The report also emphasizes the critical need for increased funding, improved diagnostics, and more effective TB treatment regimens. The impact of the COVID-19 pandemic on TB control has been substantial, disrupting healthcare services and exacerbating existing challenges. This paper provides an in-depth interpretation of the report, analyses global TB trends, updates the status of drug-resistant TB, discusses the intersection between TB and HIV, and summarizes the implications of the pandemic on TB control efforts. The report concludes with a call for intensified global action, including increased investment in research and innovation, to achieve the United Nations’ Sustainable Development Goals related to TB control. The stakes are high, but with concerted efforts, the goal of ending the TB epidemic is within reach. ^[1]

TETRAZOLE ⁽²⁾

Tetrazole, a bio isostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects.The tetrazole is the five-membered four nitrogen containing heterocyclic aromatic ring.Tetrazole play a key role in various biological properties, its like Anti-tubercular activity, Anti-bacterial activity, Anti-fungal activity, Anti-viral activity, Hypo glycemic activity, Anti-inflammatory, Analgesic activity, Anti-cancer activity, Anti-malarial activity.There are two forms:5,1H-tetrazole and 5,2H-tetrazole.The synthesis and development of new 5,1H-tetrazole with low toxicity and inhibit the growth of mycobacterium tuberculosis.The synthesis and development of new 5,1H-tetrazole with low toxicity and inhibit the growth of mycobacterium tuberculosis

METHODS AND MATERIALS:

SOFTWARE’S USED

LIGAND PREPARATION:

Ligands were obtained from ZINC or PubChem databases, or drawn using ACD/ChemSketch. They were converted to 3D using Chem3D Viewer, energy minimized in PyRx, and saved in .pdb or. mol formats for docking.

PROTEIN PREPARATION:

The target protein was retrieved from the RCSB Protein Data Bank. Water molecules and heteroatoms were removed, polar hydrogens were added, and Kollman charges were assigned using AutoDock Tools. Energy minimization was done using PyRx.

DOCKING PROCEDURE:

Molecular docking was performed using AutoDock 4.2, MGLTools 1.5.7, and PyRx 0.8. A grid box was set around the active site, and the Lamarckian Genetic Algorithm was applied. Binding affinity was evaluated, and the most negative value was considered the best binding pose.

VISUALIZATION AND ANALYSIS:

The docked complexes were analyzed using Discovery Studio Visualizer. Binding interactions and drug-likeness were assessed based on binding energy and key ADME properties.

RESULT AND DISCUSSION:

Docking studies using AutoDock 1.5.6 (5JFO) and PyRx (5JFO, 4QXM) showed that most Isoniazid-coupled 5,1H-Tetrazole derivatives had stronger binding affinities than the standards (≈ –5 to –7.6 kcal/mol).

In AutoDock, the best score was for Compound 62 (–13.464 kcal/mol), followed by 34, 33, 55, 58, and 57(all<–12kcal/mol). In PyRx, top binders for 5JFO included Compound 58 (–10.5) and 37 (–9.8), while for 4QXM, 37 (–10.6) and 58 (–10.6) led the list.

Compounds 23, 37, 55, 58, 60, 61, and 62 consistently ranked high in both software, indicating strong and stable ligand–protein interactions. These results suggest enhanced inhibitory potential over the standards, supporting further ADMET and experimental validation.

METHOD

Table:1 Auto Dock Docking Score (5jfo) Using Auto Dock1.5.6 Software

The docking study was conducted using PyRx software against two proteins, 5JFO and 4QXM. The Isoniazid-Coupled 5,1H-Tetrazole derivative compounds exhibited stronger binding affinity (more negative values) than the standard drug. The best binding score for 5JFO and 4QXM was -10.5 and -10.6.

Table:6 Docking Score (5jfo and 4qxm) Using Pyrx Software