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Thermodynamic signature for the drug binding in the minor-groove of DNA

AuthorsBarceló, Francisca; Portugal, José
Issue Date5-Sep-2016
CitationXXXIX Congreso de la SEBBM (2016)
AbstractWe have obtained complete thermodynamic profiles consisting of binding constants, free energy, enthalpy, and entropy for tbe binding of drugs in the G+C-rich regions of DNA.Such profiles are importan!in anticancer drug design because they provide information on the balance of driving forces tbat is not accessible by structural or computational metbods alone ( 1, 2]. Despite most of the small drugs tbat bind to C+G-rich sequences are intercalating agents, a variety of molecules bind directly and selectively to C+G-ricb DNA tracts tbrougb tbe minar groove without intercalation. lnterestingly, many of those molecules are active as chemotherapeutic agents by inhibiting replication or transcription. Tbe binding of drugs in tbe minar groove of either C+G-rich or A+T-rich DNA sequences is entropically driven wbile intercalation is enthalpically driven. To gain insights into the different binding signatures, we bave used UV-thermal denaturation and ITC (isothermal titration calorimetry), as well as computations of tbe bydrophobic free energy of binding, to determine tbe thermodynamic profile of drug binding to G+C-rich DNA sequences. The tbermodynamic analysis sbows tbat the binding in the minar groove of DNA is, regardless of the DNA sequence involved, always entropically-dsiven, dominated by the bydrophobic transfer of drug molecules from solution to the DNA-binding site.Direct molecular recognition between drugs and DNA through hydrogen bonding and van der Waals contacts also contributes significantly to drug-DNA complex formation.
DescriptionTrabajo presentado en el XXXIX Congreso de la SEBBM, celebrado en Salamanca, España, del 5 al 8 de septiembre de 2016
Appears in Collections:(IBMB) Comunicaciones congresos
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