DNA Minor Groove Binders: an Overview on Molecular Modeling and QSAR Approaches

Abstract

Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments.

DNA-Based Electrodes and Computational Approaches on the Intercalation Study of Antitumoral Drugs

“…On the other hand, the pentanedioic acid moiety of the MTX also forms hydrogenbond interactions with N4 of C(1), whereas N5 of pteridine forms two hydrogen-bond interactions with carbonyls of C(5) and T(4). These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42].…”

“…These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42]. The predicted MTX-DNA binding mode also corroborates with results published by Rafique et al [16], which showed through FT-IR the involvement of hydrogen-bond interactions in the intercalative binding of MTX between nitrogen bases [16].…”

DNA-Based Electrodes and Computational Approaches on the Intercalation Study of Antitumoral Drugs

“…On the other hand, the pentanedioic acid moiety of the MTX also forms hydrogenbond interactions with N4 of C(1), whereas N5 of pteridine forms two hydrogen-bond interactions with carbonyls of C(5) and T(4). These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42].…”

“…These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42]. The predicted MTX-DNA binding mode also corroborates with results published by Rafique et al [16], which showed through FT-IR the involvement of hydrogen-bond interactions in the intercalative binding of MTX between nitrogen bases [16].…”

Evaluation of Antimicrobial, Antitumor, Antioxidant Activities, and Molecular Docking Studies of Some Co(II), Cu(II), Mn(II), Ni(II), Pd(II), and Pt(II) Complexes With a Schiff Base Derived From 2‐Chloro‐5‐(trifluoromethyl)aniline

“…Groove binders, on the other hand, do not cause significant structural changes, are usually molecules with unfused aromatic rings permitting higher freedom of movement and groove compatibility [70, 71]. Minor groove binders are especially of interest, as they can function as gene regulators, inhibiting the expression of target gene by blocking their transcription [71]. The hyperchromic effect we observed, without a significant red or blue shift, suggests nonintercalative binding, most likely acting as a groove binder [54, 67, 69].…”

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids

“…We assume that such conformational flexibility could be important for the adaptability of hydrazino peptides in interaction with biomolecules, particularly nucleic acids. It is known that minor groove of the DNA is target of many non-covalent binding compounds, where beside electrostatic and van der Waals interactions, hydrogen bonding pattern is essential for a recognition process (Lauria et al 2007 ). Therefore, we plan to expand here described concept of peptidomimetics with alternating and sequential distribution of hydrazino units on series of derivatives, to probe the binding to nucleic acids.…”

DNA-Based Electrodes and Computational Approaches on the Intercalation Study of Antitumoral Drugs

“…On the other hand, the pentanedioic acid moiety of the MTX also forms hydrogenbond interactions with N4 of C(1), whereas N5 of pteridine forms two hydrogen-bond interactions with carbonyls of C(5) and T(4). These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42].…”

“…These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42]. The predicted MTX-DNA binding mode also corroborates with results published by Rafique et al [16], which showed through FT-IR the involvement of hydrogen-bond interactions in the intercalative binding of MTX between nitrogen bases [16].…”

Evaluation of Antimicrobial, Antitumor, Antioxidant Activities, and Molecular Docking Studies of Some Co(II), Cu(II), Mn(II), Ni(II), Pd(II), and Pt(II) Complexes With a Schiff Base Derived From 2‐Chloro‐5‐(trifluoromethyl)aniline

“…Groove binders, on the other hand, do not cause significant structural changes, are usually molecules with unfused aromatic rings permitting higher freedom of movement and groove compatibility [70, 71]. Minor groove binders are especially of interest, as they can function as gene regulators, inhibiting the expression of target gene by blocking their transcription [71]. The hyperchromic effect we observed, without a significant red or blue shift, suggests nonintercalative binding, most likely acting as a groove binder [54, 67, 69].…”

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids

“…We assume that such conformational flexibility could be important for the adaptability of hydrazino peptides in interaction with biomolecules, particularly nucleic acids. It is known that minor groove of the DNA is target of many non-covalent binding compounds, where beside electrostatic and van der Waals interactions, hydrogen bonding pattern is essential for a recognition process (Lauria et al 2007 ). Therefore, we plan to expand here described concept of peptidomimetics with alternating and sequential distribution of hydrazino units on series of derivatives, to probe the binding to nucleic acids.…”

DNA-Based Electrodes and Computational Approaches on the Intercalation Study of Antitumoral Drugs

“…On the other hand, the pentanedioic acid moiety of the MTX also forms hydrogenbond interactions with N4 of C(1), whereas N5 of pteridine forms two hydrogen-bond interactions with carbonyls of C(5) and T(4). These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42].…”

“…These results corroborate with the study of Yang et al [42], which showed through (UV)-VIS spectroscopy and fluorescence analysis that MTX intercalates into the double helix of DNA. In addition, a thermodynamic study developed by same authors showed that MTX promotes negative enthalpy changes (∆H) and entropy changes (∆S), demonstrating that this drug binds to DNA via hydrogen-bond interactions and van der Waals interactions [42]. The predicted MTX-DNA binding mode also corroborates with results published by Rafique et al [16], which showed through FT-IR the involvement of hydrogen-bond interactions in the intercalative binding of MTX between nitrogen bases [16].…”

Evaluation of Antimicrobial, Antitumor, Antioxidant Activities, and Molecular Docking Studies of Some Co(II), Cu(II), Mn(II), Ni(II), Pd(II), and Pt(II) Complexes With a Schiff Base Derived From 2‐Chloro‐5‐(trifluoromethyl)aniline

“…Groove binders, on the other hand, do not cause significant structural changes, are usually molecules with unfused aromatic rings permitting higher freedom of movement and groove compatibility [70, 71]. Minor groove binders are especially of interest, as they can function as gene regulators, inhibiting the expression of target gene by blocking their transcription [71]. The hyperchromic effect we observed, without a significant red or blue shift, suggests nonintercalative binding, most likely acting as a groove binder [54, 67, 69].…”

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids

“…We assume that such conformational flexibility could be important for the adaptability of hydrazino peptides in interaction with biomolecules, particularly nucleic acids. It is known that minor groove of the DNA is target of many non-covalent binding compounds, where beside electrostatic and van der Waals interactions, hydrogen bonding pattern is essential for a recognition process (Lauria et al 2007 ). Therefore, we plan to expand here described concept of peptidomimetics with alternating and sequential distribution of hydrazino units on series of derivatives, to probe the binding to nucleic acids.…”