Thermodynamics of DNA Minor Groove Binders Perspective Hasan Y. Alniss* Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates ABSTRACT: Understanding the thermodynamic and bind- ing characteristics of DNA minor groove binders (MGBs) is important for the rational design and development of novel MGBs; however, there are contradicting results in the literature regarding the thermodynamic signature of MGBs. The expansion of the thermodynamic database for MGBs in the literature was encouraging to evaluate and critically test the previously reported hypothesis that MGB binding is mainly entropically driven. In this review, the thermodynamic data of a group of MGBs published in the literature were analyzed to better understand the factors that drive minor groove recognition. Analysis of the enthalpic and entropic contributions to the free energy of binding for 20 interactions from a total of 14 different compounds reveals that MGB binding can be driven by enthalpy, entropy, or by both and that is mainly dictated by ligand structural heterogeneity. These findings could be useful in the design of MGBs for therapeutic purposes. 1. INTRODUCTION Minor groove binders (MGBs) are a class of small molecules that bind to the minor groove of duplex DNA. Some of these compounds are of natural origins, e.g., the polyamides, netropsin, and distamycin, 3 while others are synthetic compounds, e.g., thiazotropsin A 4 and the hairpin 7 structure (Figure 1). These molecules have crescent shapes that match the curvature of DNA in the minor groove and can interact noncovalently in a sequence specific fashion with the targeted DNA base sequence by a combination of hydrogen bonding to the DNA base pairs, van der Waals interactions with the walls of the minor groove, and nonspecific electrostatic interactions with the backbone of DNA. MGBs have recently found wide applications in research as a tool to control gene expression 8 by investigating the effect of turning on/off one or more genes and as potential therapeutics in anticancer and anti-infective therapy. 11 These small molecules which intervene at the nucleic acid level are capable of turning on/off gene expression without causing permanent DNA damage, which is usually observed with the currently available toxic chemotherapeutics. The significance of MGBs in anticancer and anti-infective therapy is therefore growing, for instance, MGBs are currently being developed as transcription factor antagonists for the treatment of prostate cancer 12 and as a new class of antibacterial agents for the treatment of. Clostridium difficile infections. 11,13 The crescent-shaped MGBs bind to the minor groove as a monomer or a side-by-side antiparallel dimer (Figure 2). The dimeric recognition usually distorts the DNA structure by widening the minor groove and bending the DNA helix toward the major groove, resulting in major groove compression. 8,9 These structural changes make the transcription factors unable to recognize their target in the major grooves. Such structural perturbations in the DNA helix, especially in relation to the groove dimensions, are believed to be responsible for the disruption of transcription factor-DNA interfaces via allosteric modulation. 8 Understanding the molecular basis of ligand-DNA associ- ations, particularly the structural and thermodynamic details, is of prime importance for the rational design and development of novel drugs. With the increasing availability of advanced isothermal titration calorimeters, these highly sensitive instru- ments have become widely used for the characterization of biomolecular interactions in vitro. Such studies provide a complete thermodynamic profile for bimolecular interactions in aqueous solutions and that includes the determination of the binding affinity (K), stoichiometry (N), enthalpy (ΔH), entropy (ΔS), and free energy of binding (ΔG) for the interaction. Analysis of the enthalpic and entropic contribution to the free energy of binding can reveal the molecular forces that drive complex formation. Furthermore, studying the binding thermodynamic characteristics of closely related ligand structures to a specific binding site helps to establish how modifications in the structure influence the binding affinity. Information obtained from the analysis and interpretation of thermodynamic data is useful in revealing the pharmacophore of drug which can then be used in directing the structural Received: February 12, 2018 Published: July 30, 2018 Perspective pubs.acs.org/jmc Cite This: J. Med. Chem. 2019, 62, 385-402 © 2018 American Chemical Society 385 DOI: 10.1021/acs.jmedchem.8b00233 J. Med. Chem. 2019, 62, 385-402 Downloaded via UNIV OF SHARJAH on February 17, 2019 at 12:07:05 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.