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.

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.…”

Synthesis, Biological Evaluation, and Modeling of Dimeric PPI Analogues as Novel DNA Minor Groove Binders

“…Usually electrostatic, van der Waals, hydrophobic and hydrogen bonding forces dominate the binding ability of small molecules, whereas sequence specificity is often attributed to the formation of key hydrogen bonds between a base pair and the small molecule. Another crucial structural requirement is that the ligand have a crescent shape and be able to adopt an “isohelical” conformation to fit the minor groove [3]. The X-ray crystallographic structure of the DNA dodecamer d(CGCAAATTTGCG) with a bifurcated hydrogen-bonded conformation of the AT base pairs and its complex with distamycin A was selected from the Protein Data Bank (PDB code: 2DND) for the docking study [8].…”

“…However, a subsequent phase II trial did not show any objective responses [2]. X-ray crystallographic and NMR studies on complexes of Hoechst 33258 with AT-containing oligonucleotides have shown that the drug fits the minor groove snugly, with the planar benzimidazole groups oriented parallel to the direction of the groove and each inner-facing nitrogen atom hydrogen bonding in a bifurcated manner to a pair of adjacent hydrogen-bond donors on the edge of the AT base pairs [3]. Most studies focused on the development of DNA-binding ligands with high affinity and sequence specificity.…”

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

“…Intercalators introduce strong structural perturbations in DNA structure by creating an intercalation site. These ligands contain planar heterocyclic scaffolds that stack between adjacent DNA base pairs through π-π stacking interactions [31][32][33][34][35][36][37][38][39][40][41][42].…”