| Autor: |
Qiu X; School of Pharmacy, Lanzhou University, Lanzhou 730000, China., Zhang Q; Faculty of Applied Science, Macao Polytechnic University, Macao SAR, China., Li Z; School of Pharmacy, Lanzhou University, Lanzhou 730000, China., Zhang J; School of Pharmacy, Lanzhou University, Lanzhou 730000, China., Liu H; Faculty of Applied Science, Macao Polytechnic University, Macao SAR, China. |
| Jazyk: |
angličtina |
| Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2024 Mar 28; Vol. 25 (7). Date of Electronic Publication: 2024 Mar 28. |
| DOI: |
10.3390/ijms25073764 |
| Abstrakt: |
With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors' binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors' attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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