Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Apr 3;20(4):5942-64.
doi: 10.3390/molecules20045942.

Probing the relationship between anti-Pneumocystis carinii activity and DNA binding of bisamidines by molecular dynamics simulations

Teresa Żołek  1 , Dorota Maciejewska  2 , Jerzy Żabiński  3 , Paweł Kaźmierczak  4 , Mateusz Rezler  5
Affiliations

Probing the relationship between anti-Pneumocystis carinii activity and DNA binding of bisamidines by molecular dynamics simulations

Teresa Żołek et al. Molecules. .

Abstract

The anti-Pneumocystis carinii activity of 13 synthetic pentamidine analogs was analyzed. The experimental differences in melting points of DNA dodecamer 5'-(CGCGAATTCGCG)2-3' complexes (ΔTm), and in the biological activity measured using ATP bioluminescence assay (IC50) together with the theoretical free energy of DNA-ligand binding estimated by the proposed computational protocol, showed that the experimental activity of the tested pentamidines appeared to be due to the binding to the DNA minor groove with extended AT sequences. The effect of heteroatoms in the aliphatic linker, and the sulfonamide or methoxy substituents on the compound inducing changes in the interactions with the DNA minor groove was examined and was correlated with biological activity. In computational analysis, the explicit solvent approximation with the discrete water molecules was taken into account, and the role of water molecules in the DNA-ligand complexes was defined.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The plot of ΔTm versus theoretically estimated DNA free energy of binding (−ΔGbind).
Figure 2
Figure 2
The plot of log(1/IC50) versus theoretically estimated DNA free energy of binding (−ΔGbind).
Figure 3
Figure 3
The plot of log(1/IC50) versus ΔTm for the 5'-(CGCGAATTCGCG)2-3' dodecamer-bisamidine complexes.
Figure 4
Figure 4
Illustration of conformational differences between pentamidine and its analogs in the DNA minor groove. Pentamidine is shown in red, and the ligands are shown in blue. (A) compound 1; (B) compound 6; (C) compound 7; (D) compound 9; (E) compound 12; (F) compound 13.
Figure 5
Figure 5
Location of ligands in the minor groove. (A) deformation of DNA by 7; (B) deformation of DNA by 9; (C) deformation of DNA by 12; (D) deformation of DNA by 13; (E) fitted conformation of 5; (F) deformation of DNA by 8.
Figure 6
Figure 6
Stereo (cross-eye) views of the hydration surface (water density in red) associated with the movement of compound 5 within the 5'-(CGCGAATTCGCG)2-3' dodecamer. (A) In the time frames between 1.5 and 2 ns MD–there are no direct H-bond contacts between the DNA bases and both amidinium groups; (B) In the time frames between 5 and 10 ns MD–both amidinium groups in ligand make direct H-bond contacts with the DNA bases.
Figure 7
Figure 7
A view of hydration sites for compound 5 in the minor groove (red lines—hydrogen bonds; length [Å]). (A) hydration sites H1–H3; (B) hydration sites H4–H5; (C) hydration sites H6–H7.
Figure 8
Figure 8
A view of five hydration sites for compound 10 in the minor groove (red lines—hydrogen bonds; length [Å]). (A) hydration sites H1–H2; (B) hydration sites H4–H5; (C) hydration site H7.
Figure 9
Figure 9
A view of three hydration sites for compound 11 in the minor groove (red lines—hydrogen bonds; length [Å]). (A) hydration site H2; (B) hydration sites H4–H5; (C) lack of hydration sites H6–H7.
Figure 10
Figure 10
A view of one hydration site for compound 8 in the minor groove (red lines–hydrogen bonds; length [Å]).
See this image and copyright information in PMC

References

    1. Tidwell R.R., Jones S.K., Geratz J.D., Ohemeng K.A., Cory M., Hall J.E. Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia. J. Med. Chem. 1990;33:1252–1257. doi: 10.1021/jm00166a026. - DOI - PubMed
    1. Fishman J.A. Treatment of infection due to Pneumocystis carinii. Antimicrob. Agents Chemother. 1998;42:1309–1314. - PMC - PubMed
    1. Ismail M.A., Arafa R.K., Brun R., Wenzler T., Miao Y., Wilson W.D., Bridges A., Hall J.E., Boykin D.W. Synthesis, DNA affinity, and antiprotozoal activity of linear dications: Terphenyl diamidines and analogues. J. Med. Chem. 2006;49:5324–5332. doi: 10.1021/jm060470p. - DOI - PubMed
    1. Mathis A.M., Holman J.L., Sturk L.M., Ismail M.A., Boykin D.W., Tidwell R.R., Hall J.E. Acumulation and intracelular distribution of Antitrypasomal diamidine compounds DB75 and DB820 in African Trypanosomes. Antimicrob. Agents Chemother. 2006;50:2185–2191. doi: 10.1128/AAC.00192-06. - DOI - PMC - PubMed
    1. Brendle J.J., Outlaw A., Kumar A., Boykin D.W., Patrick D.A., Tidwell R.R., Werbovetz K.A. Antileishmanial activities of several classes of aromatic dications. Antimicrob. Agents Chemother. 2002;46:797–807. doi: 10.1128/AAC.46.3.797-807.2002. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources