Abstract
Molecular docking studies have been performed to assess the antimicrobial potential of three 1,3,4-thiadiazole derivatives containing azulene rings. The simulations were conducted on Mycobacterium tuberculosis DNA gyrase, Staphylococcus aureus DNA gyrase, and Escherichia coli DNA adenine methylase. The relationships between the structures of compounds and their potential antimicrobial activity were investigated. Interactions with amino acid residues from the active binding site were elucidated and the results of docking are reported in terms of docking score. Better docking scores are obtained for the investigated compounds than for the natural ligand, (4S)-2-methyl-2,4-pentanediol, in the case of the Mycobacterium tuberculosis. Two of the studied ligands present better binding affinities against Escherichia coli than the co-crystallized ones. Regarding S. aureus gyrase, the thiadiazole derivatives exhibit lower docking scores and fewer interactions than the aminobenzimidazole urea inhibitor. Our study can be useful to screen and design similar hybrid active compounds.
Highlights
Heterocyclic compounds, such as thiadizoles, play an important role among organic compounds possessing pharmacological activity, with potential applications in medicinal chemistry
Some hybrid thiadiazoles-based structures (e.g., 2-phenylamino5-(4-fluorophenyl)-1,3,4-thiadiazole) are reported as pharmacophore systems, with antituberculosis activity against Mycobacterium tuberculosis [1]. 2-Amino-1,3,4-thiadiazole is reported as a promising scaffold to design antimicrobial agents [2]
The protein fragments were imported from the Protein Data Bank: 3M4I: crystal structure of the second part of the Mycobacterium tuberculosis DNA gyrase reaction core: the TOPRIM domain at 1.95 Å resolution, containing the co-crystallized): (4S)-2-methyl2,4-pentanediol [4]; 4P8O: Staphylococcus aureus gyrase bound to an aminobenzimidazole urea inhibitor (1-ethyl-3-[5-(5-fluoropyridin-3-yl)-7-(pyrimidin2-yl)-1H-benzimidazol-2-yl]ure a) [5], and 4RTO: complex of Escherichia coli DNA Adenine Methyltransferase (DAM) with Sinefungin and with DNA containing proximal Pap Regulon Sequence [6]
Summary
Heterocyclic compounds, such as thiadizoles, play an important role among organic compounds possessing pharmacological activity, with potential applications in medicinal chemistry. 2-Amino-1,3,4-thiadiazole is reported as a promising scaffold to design antimicrobial agents [2]. Some hybrid thiadiazoles-based structures (e.g., 2-phenylamino5-(4-fluorophenyl)-1,3,4-thiadiazole) are reported as pharmacophore systems, with antituberculosis activity against Mycobacterium tuberculosis [1]. Starting from such premises, the goal of this study was to examine some hybrid structures containing azulene and thiadiazoles, by computational means as a molecular docking approach to realize a virtual screening for the assessment of their potential biological activity. We intend to evaluate their possible applications in the field of medicinal chemistry
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