In silico evaluation of natural compounds to confirm their anti-DNA gyrase activity

• Published in: Nucleus (Calcutta) Vol. 66; no. 2; pp. 167 - 182
• Main Authors: Kumar, Reetesh, Srivastava, Yogesh, Maji, Somnath, Siddiqui, Seemab, Tyagi, Rajeev Kumar, Muthuramalingam, Pandiyan, Singh, Sunil Kumar, Tiwari, Savitri, Verma, Geetika, de Toledo Thomazella, Daniela Paula, Shin, Hyunsuk, Prajapati, Dinesh Kumar, Rai, Pankaj Kumar, Beura, Samir Kumar, Panigrahi, Abhishek Ramachandra, de Moraes, Fabio Rogerio, Rao, Pasupuleti Visweswara
• Format: Journal Article
• Language: English
• Published: New Delhi Springer India 01.08.2023; Springer Nature B.V
• Subjects: Antibacterial activity; Antibacterial agents; Antibiotic resistance; Antibiotics; Biomedical and Life Sciences; Cell Biology; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA topoisomerase; Drug resistance; Life Sciences; Molecular modelling; Original Article; Pharmacokinetics; Public health; Toxicity; Zinc database; ADMET; DNA gyrase; Antibiotic resistance
• ISSN: 0029-568X; 0976-7975
• DOI: 10.1007/s13237-023-00426-6

The slow clearance of bacteria owing to drug resistance to the currently available antibiotics has been a global public health issue. The development of antibiotic resistance in Staphylococcus aureus has become prevalent in community-acquired infections, posing a significant challenge. DNA gyrase, an enzyme essential in all bacteria but absent in higher eukaryotes, emerges as an attractive target for novel antibacterial agents. This type II topoisomerase introduces negative supercoils in double-stranded DNA, at the expense of ATP, during DNA replication. In this study, we conducted a comprehensive screening of natural compound libraries from the ZINC database using different computational approaches targeting DNA gyrase activity. We identified five promising compounds following a detailed screening of drug-like compounds using pharmacokinetic-based studies, including the determination of the compound absorption, distribution, metabolism, excretion, and toxicity. Furthermore, based on protein–ligand docking studies, we showed the position, orientation, and binding affinity of the selected compounds within the active site of DNA gyrase. Overall, our study provides a primary reference to explore the molecular mechanisms associated with the antibacterial activity of the selected compounds, representing an important step toward the discovery of novel DNA gyrase inhibitors. Further investigation involving structural optimization as well as comprehensive in vivo and in vitro evaluations are necessary to fully explore the potential of these chemicals as effective antibacterial agents. Graphical abstract