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

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dc.contributor.authorAlniss, H.Y.
dc.contributor.authorAl-Jubeh, H.M.
dc.contributor.authorMsallam, Y.A.
dc.contributor.authorSiddiqui, R.
dc.contributor.authorMakhlouf, Z.
dc.contributor.authorRavi, A.
dc.contributor.authorHamdy R.
dc.date.accessioned2024-05-19T14:33:21Z
dc.date.available2024-05-19T14:33:21Z
dc.date.issued2024
dc.departmentİstinye Üniversitesien_US
dc.description.abstractAntimicrobial 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. © 2024 Elsevier Masson SASen_US
dc.description.sponsorshipNational Cancer Institute, NCI; University of Sharjah, UOS; 2101110149, 2401110195en_US
dc.description.sponsorshipThis work was supported by a grant from the Research Funding Department, University of Sharjah-UAE (grant number: 2101110149& 2401110195)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.We would like to thank the National Cancer Institute (NCI), Bethesda, Maryland, USA, for conducting the in vitro anticancer screening using a panel of 60 cancer cell lines.en_US
dc.description.sponsorshipThis work was supported by a grant from the Research Funding Department, University of Sharjah-UAE (grant number: 2101110149 & 2401110195)en_US
dc.identifier.doi10.1016/j.ejmech.2024.116440
dc.identifier.issn0223-5234
dc.identifier.scopus2-s2.0-85191288152en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2024.116440
dc.identifier.urihttps://hdl.handle.net/20.500.12713/4198
dc.identifier.volume271en_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherElsevier Masson s.r.l.en_US
dc.relation.ispartofEuropean Journal of Medicinal Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240519_kaen_US
dc.subjectAntimicrobial Resistanceen_US
dc.subjectChemotherapy Resistanceen_US
dc.subjectDna Denaturationen_US
dc.subjectIsothermal Titration Calorimetry (Itc)en_US
dc.subjectMinor Groove Binderen_US
dc.subjectMolecular Modellingen_US
dc.titleStructure-based drug design of DNA minor groove binders and evaluation of their antibacterial and anticancer propertiesen_US
dc.typeArticleen_US

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