Structure-based drug design of DNA minor groove binders and evaluation of their antibacterial and anticancer properties.

Autor: Alniss HY; College of Pharmacy, Department of Medicinal Chemistry, University of Sharjah, 27272, Sharjah, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates. Electronic address: halniss@sharjah.ac.ae., Al-Jubeh HM; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Msallam YA; College of Pharmacy, Department of Medicinal Chemistry, University of Sharjah, 27272, Sharjah, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Siddiqui R; Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University Edinburgh, EH14 4AS, United Kingdom; Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul, 34010, Turkey., Makhlouf Z; College of Medicine, Department of Clinical Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Ravi A; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Hamdy R; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Soliman SSM; College of Pharmacy, Department of Medicinal Chemistry, University of Sharjah, 27272, Sharjah, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, 27272, Sharjah, United Arab Emirates., Khan NA; Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul, 34010, Turkey. Electronic address: naveed5438@gmail.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 May 05; Vol. 271, pp. 116440. Date of Electronic Publication: 2024 Apr 24.
DOI: 10.1016/j.ejmech.2024.116440
Abstrakt: Antimicrobial and chemotherapy resistance are escalating medical problem of paramount importance. Yet, research for novel antimicrobial and anticancer agents remains lagging behind. With their reported medical applications, DNA minor groove binders (MGBs) are worthy of exploration. In this study, the approach of structure-based drug design was implemented to generate 11 MGB compounds including a novel class of bioactive alkyne-linked MGBs. The NCI screening protocol was utilized to evaluate the antitumor activity of the target MGBs. Furthermore, a variety of bactericidal, cytopathogenicity, MIC90, and cytotoxicity assays were carried out using these MGBs against 6 medically relevant bacteria: Salmonella enterica, Escherichia coli, Serratia marcescens, Bacillus cereus, Streptococcus pneumoniae and Streptococcus pyogenes. Moreover, molecular docking, molecular dynamic simulations, DNA melting, and isothermal titration calorimetry (ITC) analyses were utilized to explore the binding mode and interactions between the most potent MGBs and the DNA duplex d(CGACTAGTCG) 2 . NCI results showed that alkyne-linked MGBs (26 & 28) displayed the most significant growth inhibition among the NCI-60 panel. In addition, compounds MGB3, MGB4, MGB28, and MGB32 showed significant bactericidal effects, inhibited B. cereus and S. enterica-mediated cytopathogenicity, and exhibited low cytotoxicity. MGB28 and MGB32 demonstrated significant inhibition of S. pyogenes, whereas MGB28 notably inhibited S. marcescens and all four minor groove binders significantly inhibited B. cereus. The ability of these compounds to bind with DNA and distort its groove dimensions provides the molecular basis for the allosteric perturbation of proteins-DNA interactions by MGBs. This study shed light on the mechanism of action of MGBs and revealed the important structural features for their antitumor and antibacterial activities, which are important to guide future development of MGB derivatives as novel antibacterial and anticancer agents.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hasan Y. Alniss has patent pending to University of Sharjah. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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