Investigating the interaction of Aquimarins, Svetamycin C, Smenothiazole A, Atrovimycin A and Atratumycin with membrane and intracellular targets of Mycobacterium tuberculosis by molecular docking method

Objective: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), remains a significant global health threat and one of the highest causes of infectious mortality. The rise in drug-resistant Mtb strains has intensified the demand for new therapeutic agents that can effectively target both membrane and intracellular components of the pathogen. Traditional antibiotics often fall short due to resistance mechanisms and limited penetration of bacterial barriers. In response, our study explores five natural compounds—Aquimarins, Svetamycin C, Smenothiazole A, Atrovimycin A, and Atratumycin—as potential alternatives with unique structural properties and demonstrated antimicrobial activities. Using molecular docking methods, we investigated the binding affinities and interaction patterns of these compounds against essential targets in Mtb, such as InhA, DNA gyrase, and membrane-associated proteins. InhA, an enoyl-ACP reductase enzyme, is vital in Mtb’s fatty acid synthesis, while DNA gyrase plays a critical role in bacterial DNA replication. Membrane-associated proteins are also essential for maintaining Mtb’s robust cell wall structure and facilitating nutrient transport, making them prime therapeutic targets. Our findings suggest that these natural products exhibit promising binding interactions with the selected targets, offering potential pathways to disrupt Mtb growth and enhance TB treatment options. Materials and Methods: A comprehensive in silico approach was employed, utilizing molecular docking to evaluate the interactions of the selected compounds with specific Mtb targets. The ۳D structures of Aquimarins, Svetamycin C, Smenothiazole A, Atrovimycin A, and Atratumycin were retrieved from PubChem and optimized using energy minimization. The protein targets were selected based on their critical role in Mtb survival and pathogenesis, including Enoyl-ACP reductase (InhA), DNA gyrase, and membrane proteins such as MmpL۳. The docking simulations were performed using AutoDock Vina, and the binding affinities were evaluated based on the lowest binding free energy values. Visualization of interactions, including hydrogen bonds and hydrophobic contacts, was carried out using PyMOL and Discovery Studio software. Statistical analysis was conducted using ANOVA, with a significance threshold set at p < ۰.۰۵. Results: The molecular docking analysis revealed significant binding affinities of all tested compounds with Mtb targets, suggesting strong inhibitory potential against Mycobacterium tuberculosis (Mtb). Aquimarins exhibited the highest affinity towards MmpL۳, with a binding energy of -۱۰.۵ kcal/mol (p < ۰.۰۱). Svetamycin C showed notable interactions with DNA gyrase, achieving a binding energy of -۹.۸ kcal/mol, characterized by strong hydrogen bonding with key residues (p < ۰.۰۵). Smenothiazole A demonstrated a high affinity for InhA, with a binding energy of -۸.۹ kcal/mol, indicating potential efficacy as an enoyl-ACP reductase inhibitor. Atrovimycin A and Atratumycin, although showing moderate interactions, displayed binding energies of -۸.۲ kcal/mol and -۷.۹ kcal/mol, respectively, with membrane-associated proteins. The comparative analysis showed statistically significant differences in the binding affinities of these compounds across the different targets. Aquimarins and Svetamycin C had the strongest overall interactions, making them the most promising candidates for further development. The docking studies also highlighted critical residues involved in the binding interactions, such as Ser۹۴ and Gly۹۶ in DNA gyrase, which are known sites for drug binding and resistance mechanisms in Mtb. These findings suggest the compounds have potential as effective anti-tuberculosis agents. Conclusion: This study provides valuable insights into the potential of five natural compounds—Aquimarins, Svetamycin C, Smenothiazole A, Atrovimycin A, and Atratumycin—as novel therapeutic agents against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). The strong binding affinities observed, particularly for Aquimarins and Svetamycin C, suggest their significant potential for targeting essential membrane and intracellular proteins of Mtb, including key enzymes and structural components critical to bacterial survival and replication. These compounds’ interactions with Mtb proteins such as InhA and DNA gyrase indicate that they may disrupt vital cellular processes, such as lipid biosynthesis and DNA

کلیدواژه ها:

Mycobacterium tuberculosis ، molecular docking ، Aquimarins ، Svetamycin C ، Smenothiazole A ، Atrovimycin A ، Atratumycin ، drug-resistant ، therapeutic agents ، binding affinities ، InhA ، DNA gyrase ، membrane-associated proteins ، anti-tuberculosis agents