Docking Studies on DNA Intercalators

Abstract

DNA is an important target for the treatment of multiple pathologies, most notably cancer. In particular, DNA intercalators have often been used as anticancer drugs. However, despite their relevance to drug discovery, only a few systematic computational studies were performed on DNA-intercalator complexes. In this work we have analyzed ligand binding sites preferences in 63 high resolution DNA-intercalator complexes available in the PDB and found that ligands bind preferentially between G and C and between the C and A base pairs (70% and 11%, respectively). Next, we examined the ability of AUTODOCK to accurately dock ligands into preformed intercalation sites. Following the optimization of the docking protocol, AUTODOCK was able to generate conformations with RMSD values <2.00 Å with respect to crystal structures in ∼80% of the cases while focusing on the preformed binding site (small grid box) or on the entire DNA structure (large grid box). In addition, a top ranked conformation with an RMSD < 2.00 Å was identified in 75% and 60% of the cases using small and large docking boxes, respectively. Moreover, under the large docking box setting AUTODOCK was able to successfully distinguish between the intercalation site and the minor groove site. However, in all cases the crystal structures and poses tightly clustered around it had a lower score than the best scoring poses suggesting a potential scoring problem with AUTODOCK. A close examination of all cases where the top ranked pose had an RMSD value >2.00 Å suggests that AUTODOCK may overemphasize the hydrogen bonding term. A decision tree was built to identify ligands which are likely to be accurately docked based on their characteristics. This analysis revealed that AUTODOCK performs best for intercalators characterized by a large number of aromatic rings, low flexibility, high molecular weight, and a small number of hydrogen bond acceptors. Finally, for canonical B-DNA structures (where preformed sites are unavailable), we demonstrated that intercalation sites could be formed by inserting an anthracene moiety between the (anticipated) site-flanking base pairs and by relaxing the structure using either energy minimization or preferably molecular dynamics simulations. Such sites were suitable for the docking of different intercalators by AUTODOCK.

Theoretical studies on binding modes of copper-based nucleases with DNA

“…The binding of the studied copper nucleases in type A to DNA were largely determined by both the electrostatic (ΔEele) and the van der Waals (ΔEvdw) energy terms.The electrostatic interaction (ΔEele) of A1-dpq with DNA (-788.09 kcal/mol) was larger than that of A1-bpy with DNA (-760.91 kcal/mol); and it was considerably larger compared to A1-phen with DNA adduct (-481.85 kcal/mol). It was also the case in ΔEele of A3-bpy and A4-bpy with DNA (-864.25 and −422.58 kcal/mol, respectively), which was larger than that of A3-phen and A4-phen with DNA (-773 80. and −240.48 kcal/mol, respectively), but the ΔEele of A2-phen (-596.75 kcal/mol) with DNA was larger than that of A2-bpy (-574.54 kcal/mol) with DNA.…”

“…This phenomenon can be explained by the fact that the DNA intercalator does not intercalate with the bases of the normal DNA molecule [79,80]. Previous studies found that, provided target DNA with an artificial intercalation gap [34,74], dockings pointed to the correct binding mode as the energetically most favorable result.…”

“…Unlike the groove binding, intercalation of a compound to DNA requires a significant distortion of the DNA's structure [79][80][81]. If there is a specific site on DNA for a docking study of ligand intercalation, then the site can be formed prior to docking.…”

Sulfonated Schiff base Sn(IV) complexes as potential anticancer agents

“…Molecular docking is an important tool in the drug design and performs a very essential role in knowing the mechanistic process of DNA-drug communications, which forecasts the recommended alignment of a given drug to DNA, thereby providing the visible representation of the executed drug to DNA [115,116]. Thus, to be able to comprehend the mechanistic process engaged in the interaction of our complexes 1 and 2 to DNA, they were successively docked within the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer (PDB ID: 1BNA).…”

Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity

“…All this evidence globally confirms that the nature of the NN co-ligand is the main factor in defining the DNA binding mode of these species. [52,53]). Thus a quantitative use of the binding affinities in Table 5 as predictors to discriminate between species with dissimilar DNA binding modes is not advised.…”