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
. 2024 Sep 19:23:11769351241276759.
doi: 10.1177/11769351241276759. eCollection 2024.

Computational Insights into Captopril's Inhibitory Potential Against MMP9 and LCN2 in Bladder Cancer: Implications for Therapeutic Application

Sanjida Kabir Annana  1 , Jannatul Ferdoush  2 , Farzia Lamia  1 , Ayan Roy  3 , Pallab Kar  4 , Monisha Nandi  5 , Maliha Kabir  3 , Ayan Saha  3
Affiliations

Computational Insights into Captopril's Inhibitory Potential Against MMP9 and LCN2 in Bladder Cancer: Implications for Therapeutic Application

Sanjida Kabir Annana et al. Cancer Inform. .

Abstract

Objectives: Captopril is a commonly used therapeutic agent in the management of renovascular hypertension (high blood pressure), congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy. Captopril has been found to interact with proteins that are significantly associated with bladder cancer (BLCA), suggesting that it could be a potential medication for BLCA patients with concurrent hypertension.

Methods: DrugBank 5.0 was utilized to identify the direct protein targets (DPTs) of captopril. STRING was used to analyze the multiple protein interactions. TNMPlot was used for comparing gene expression in normal, tumor, and metastatic tissue. Then, docking with target proteins was done using Autodock. Molecular dynamics simulations were applied for estimate the diffusion coefficients and mean-square displacements in materials.

Results: Among all these proteins, MMP9 is observed to be an overexpressed gene in BLCA and its increased expression is linked to reduced survival in patients. Our findings indicate that captopril effectively inhibits both the wild type and common mutated forms of MMP9 in BLCA. Furthermore, the LCN2 gene, which is also overexpressed in BLCA, interacts with captopril-associated proteins. The overexpression of LCN2 is similarly associated with reduced survival in BLCA. Through molecular docking analysis, we have identified specific amino acid residues (Tyr179, Pro421, Tyr423, and Lys603) at the active pocket of MMP9, as well as Tyr78, Tyr106, Phe145, Lys147, and Lys156 at the active pocket of LCN2, with which captopril interacts. Thus, our data provide compelling evidence for the inhibitory potential of captopril against human proteins MMP9 and LCN2, both of which play crucial roles in BLCA.

Conclusion: These discoveries present promising prospects for conducting subsequent validation studies both in vitro and in vivo, with the aim of assessing the suitability of captopril for treating BLCA patients, irrespective of their hypertension status, who exhibit elevated levels of MMP9 and LCN2 expression.

Keywords: Captopril; LCN2; MMP9; bladder cancer (BLCA); hypertension; inhibition; molecular dynamics simulation.

PubMed Disclaimer

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Relationship between captopril and captopril-associated genes. (A) Protein-protein interaction (PPI) network of captopril target genes (ACE, MMP2, MMP9, BDKRB1, LTA4H) from STRING. (B) STITCH and (C) NetworkAnalyst visualization of direct interactions between Captopril and LTA4H, ACE, MMP2, and MMP9.
Figure 2.
Figure 2.
mRNA expression profile of captopril associated genes in BLCA. Box plot showing the expression of genes (A) ACE (B) MMP2 (C) MMP9 (D) LTA4H and (E) BDKRB1. RED color indicates bladder cancer and GREEN color means non-cancer/Normal. The X-axis of the plot shows normal and tumor samples and the Y-axis shows gene expression. The thick line in the middle represents the median, and the upper and lower limits of the box represent the third and first quartile respectively. Statistical analysis is Mann-Whitney U test (P values < .05 = *, <.005 = **, <.0005 = ***). (F) Expression (Transcript per million) of MMP9 in Normal weight, Extreme weight, Obese and Extreme obese. Normal weight = BMI greater than equal to 18.5 and BMI less than 25; Extreme weight = BMI greater than equal to 25 and BMI less than 30; Obese = BMI greater than equal to 30 and BMI less than 40; Extreme obese = BMI greater than 40. Statistical analysis is Mann-Whitney U test (P values < .05 = *, <.005 = **, <.0005 = ***).
Figure 3.
Figure 3.
Association of captopril associated genes with overall survival in BLCA patients. Survival risk curves are shown for captopril DPT genes (A) ACE (B) MMP2 (C) MMP9 (D) LTA4H (E) BDKRB1 expression in BLCA using KM-plotter. The expression ranges of the probes for ACE, MMP2, MMP9, LTA4H, and BDKRB1 are 26-2345, 160-98 392, 2-63 2587, 828-7249, and 1-1862, respectively. The cutoff values for these genes were 241, 8323, 207, 2195, and 22. Low and high expression level of genes are drawn in black and red respectively. X-axis shows per months or time and Y-axis shows probability of survival. In KM-plotter the threshold for the high and low gene expression cohorts is automatically calculated.
Figure 4.
Figure 4.
Identification of common DPTs of captopril and overexpressed genes in BLCA for assessing the benefits of captopril use. (A) Interaction of DPTs captopril with other proteins. (B) Common proteins between overexpressed genes in BCLA and interacting proteins with captopril DPTs. (C) Expression of LCN2 gene in BLCA and normal tissue. (P < .05). (D) Survival risk curves are shown for LCN2 expression in BLCA using KM-plotter. Expression range of the probe is 0 to 228 457 and cut-off is 707. Abbreviations: DPTs, direct protein targets; BLCA, bladder cancer.
Figure 5.
Figure 5.
Interaction profile of captopril-MMP9 and captopril-LCN2 complexes. (A) Molecular docking of captopril with MMP9. Blue and brown spheres represent MMP9 and captopril, respectively. (B) Molecular interaction of captopril-MMP9 complex. Hydrophobic interactions are represented as gray dashed lines and hydrogen bonds are shown as blue lines. Green dashed lines show π-stacking interactions. Yellow dashed lines represent salt bridges. (C) Molecular docking of captopril with LCN2. Gray and brown spheres represent LCN2 and captopril, respectively. (D) Molecular interaction of captopril-LCN2 complex. Hydrophobic interactions and hydrogen bonds are represented as gray dashed lines and blue lines, respectively.
Figure 6.
Figure 6.
MD simulations of unbound protein MMP9, captopril-MMP9 complex, unbound protein LCN2, and captopril-LCN2 complex. (A) RMSD analysis of unbound MMP9 and captopril-MMP9 complex for 120 ns of MD simulations. (B) RMSF analysis of of unbound MMP9 and captopril-MMP9 complex for 120 ns of MD simulations. (C) RMSD analysis of unbound LCN2 and captopril-LCN2 complex for 120 ns of MD simulations. (D) RMSF analysis of unbound LCN2 and captopril-LCN2 complex for 120 ns of MD simulations. Abbreviations: RMSD, root mean square deviation; RMSF, root mean square fluctuation.
Figure 7.
Figure 7.
Principal component analysis (PCA) on the MD trajectories of unbound proteins and protein-ligand complexes in the phase spaces. (A) unbound protein MMP9. (B) captopril-MMP9 complex. (C) unbound protein LCN2. (D) captopril-LCN2 complex. Abbreviation: PC, principal component.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Zhou L, Xu J, Song Y, Gao Y, Chen X. Preparation and in vitro release performance of sustained-release captopril/chitosan-gelatin net-polymer microspheres. J Ocean Univ China. 2007;6:249-254.
    1. Holman R, Turner R, Stratton I. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J. 1998;317:713-720. - PMC - PubMed
    1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462. - PubMed
    1. Volpert OV, Ward WF, Lingen MW, et al.. Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Investig. 1996;98:671-679. - PMC - PubMed
    1. Karagkouni D, Paraskevopoulou MD, Tastsoglou S, et al.. DIANA-LncBase v3: indexing experimentally supported miRNA targets on non-coding transcripts. Nucleic Acids Res. 2020;48:D101-D110. - PMC - PubMed

LinkOut - more resources