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
. 2023 Nov 22;28(23):7705.
doi: 10.3390/molecules28237705.

Antifungal Constituents of Piper crocatum and Their Activities as Ergosterol Biosynthesis Inhibitors Discovered via In Silico Study Using ADMET and Drug-Likeness Analysis

Tessa Siswina  1   2 , Mia Miranti Rustama  3 , Dadan Sumiarsa  1 , Eti Apriyanti  1 , Hirofumi Dohi  4 , Dikdik Kurnia  1
Affiliations

Antifungal Constituents of Piper crocatum and Their Activities as Ergosterol Biosynthesis Inhibitors Discovered via In Silico Study Using ADMET and Drug-Likeness Analysis

Tessa Siswina et al. Molecules. .

Abstract

Along with the increasing resistance of Candida spp. to some antibiotics, it is necessary to find new antifungal drugs, one of which is from the medicinal plant Red Betel (Piper crocatum). The purpose of this research is to isolate antifungal constituents from P. crocatum and evaluate their activities as ergosterol biosynthesis inhibitors via an in silico study of ADMET and drug-likeness analysis. Two new active compounds 1 and 2 and a known compound 3 were isolated, and their structures were determined using spectroscopic methods, while their bioactivities were evaluated via in vitro and in silico studies, respectively. Antifungal compound 3 was the most active compared to 1 and 2 with zone inhibition values of 14.5, 11.9, and 13.0 mm, respectively, at a concentration of 10% w/v, together with MIC/MFC at 0.31/1.2% w/v. Further in silico study demonstrated that compound 3 had a stronger ΔG than the positive control and compounds 1 and 2 with -11.14, -12.78, -12.00, and -6.89 Kcal/mol against ERG1, ERG2, ERG11, and ERG24, respectively, and also that 3 had the best Ki with 6.8 × 10-3, 4 × 10-4, 1.6 × 10-3, and 8.88 μM. On the other hand, an ADMET analysis of 1-3 met five parameters, while 1 had one violation of Ro5. Based on the research data, the promising antifungal constituents of P. crocatum allow P. crocatum to be proposed as a new antifungal candidate to treat and cure infections due to C. albicans.

Keywords: ADMET; Piper crocatum; antifungal; drug-likeness analysis; ergosterol.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of compound 1, the HMBC, and 1H-1H COSY correlations.
Figure 2
Figure 2
Structure of compound 2 and the HMBC and 1H-1H COSY correlations.
Figure 3
Figure 3
Structure of stigmasterol (3) and the HMBC and 1H-1H COSY correlations.
Figure 4
Figure 4
Enzymes of ERG1 (EC.1.14.14.17) (A), ERG2 (EC. 5.3.3.5) (B), ERG11 (EC.1.14.14.154) (C), and ERG24 (EC.1.3.1.70) (D) as macromolecules or protein targets in molecular docking.
Figure 5
Figure 5
Three-dimensional structure of terbinafine (4), amorolfine (5), and ketoconazole (6) as positive control ligands in molecular docking.
Figure 6
Figure 6
Molecular docking from terbinafine (A), ligands 1 (B), 2 (C), and 3 (D) against ERG1.
Figure 7
Figure 7
Molecular docking from amorolfine (A), ligands 1 (B), 2 (C), and 3 (D) against ERG2.
Figure 8
Figure 8
Molecular docking from ketoconazole (A), ligands 1 (B), 2 (C), and 3 (D) against ERG11.
Figure 9
Figure 9
Molecular docking from amorolfine (A), ligands 1 (B), 2 (C), and 3 (D) against ERG24.
Figure 10
Figure 10
Ergosterol pathways in fungal, with squalene (7), squalene 2,3-epoxidase (8), lanosterol (9), 4,4-Dimethylcholestas-8,12,24-trienol (10), 4,4-Dimethylzymosterol (11), zymosterol (12), episterol (13), ergosta-5,7,24 (28)trienol (14), ergosta-5,7,22,24 (28)tetraenol (15), and ergosterol (16) with the affected enzymes [82].
Figure 11
Figure 11
P. crocatum leaves (personal collection).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Tsai P.W., Chen Y.T., Hsu P.C., Lan C.Y. Study of Candida albicans and Its Interactions with The Host: A Mini Review. Biomed. J. 2013;3:51–64. doi: 10.1016/j.biomed.2012.12.004. - DOI
    1. Sardi J.C.O., Scorzoni L., Bernardi T., Fusco-Almeida A.M., Mendes Giannini M.J.S. Candida Species: Current Epidemiology, Pathogenicity, Biofilm Formation, Natural Antifungal Products and New Therapeutic Options. J. Med. Microbiol. 2013;62:10–24. doi: 10.1099/jmm.0.045054-0. - DOI - PubMed
    1. Arthington-Skaggs B.A., Jradi H., Desai T., Morrison C.J. Quantitation of Ergosterol Content: Novel Method for Determination of Fluconazole Susceptibility of Candida albicans. J. Clin. Microbiol. 1999;37:3332–3337. doi: 10.1128/JCM.37.10.3332-3337.1999. - DOI - PMC - PubMed
    1. Flowers S.A., Colón B., Whaley S.G., Schuler M.A., David Rogers P. Contribution of Clinically Derived Mutations in ERG11 to Azole Resistance in Candida albicans. Antimicrob. Agents Chemother. 2015;59:450–460. doi: 10.1128/AAC.03470-14. - DOI - PMC - PubMed
    1. French L., Horton J., Matousek M. Abnormal Vaginal Discharge: What Does and Does Not Work in Treating Underlying Causes. J. Fam. Pract. 2004;53:890–903. - PubMed

LinkOut - more resources