Current issue
Online first
Archive
About the Journal
Editorial Office
Editorial Board
Publisher
Reviewers
Editorial policies
Ethical standards and procedures
Abstracting and indexing
Contact
Subscription
Instructions for authors
Article processing charge (APC)
English language editing services
Books and Events
Books
Events
RESEARCH PAPER
Integrated analysis of usnic acid as a potential inhibitor of dengue NS2B/NS3 protease: DFT, molecular docking, MEP, ADMET, and drug-likeness evaluation
1
Sekolah Tinggi Ilmu Farmasi Riau, Pekanbaru, Riau, Indonesia
These authors had equal contribution to this work
Submission date: 2025-03-12
Final revision date: 2025-09-11
Acceptance date: 2025-12-31
Publication date: 2026-05-22
KEYWORDS
TOPICS
ABSTRACT
Background:
The present study aimed to evaluate the inhibitory capability of 10 pyrazole-usnic acid derivatives against dengue virus serotype 2 (DENV-2) NS2B/NS3 serine protease. The crystallographic structure model of the protease enzyme (PDB code: 2FOM) was used to conduct molecular docking studies of pyrazole-usnic acid derivatives with target proteins. Computational analysis was performed using the Molecular Operating Environment program, Gaussian View software, and ADMETLab platform.
Material and methods:
The inhibitory potential of the derivatives was tested by molecular docking using panduratin A as the positive control, together with density functional theory, molecular electrostatic potential analysis, drug-likeness assessment, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling.
Results:
Among the tested derivatives, compounds 5 and 6 exhibited the most promising inhibitory effects against DENV-2 NS2B/NS3 serine protease. The binding free energy values for these compounds were –7.320 and –7.477 kcal/mol, respectively. These two compounds shared multiple amino acid residues with panduratin A, which was used as a reference inhibitor. Compounds 5 and 6 also displayed negative electrostatic regions surrounding their oxygen atoms, with gap energies of 0.133 and 0.137 eV and dipole moment values of 3.237 and 2.806 D, respectively.
Conclusions:
These computational findings suggest that compounds 5 and 6 may serve as preliminary candidates for dengue virus inhibition. However, further clinical and experimental studies are required to confirm their efficacy and safety.
The present study aimed to evaluate the inhibitory capability of 10 pyrazole-usnic acid derivatives against dengue virus serotype 2 (DENV-2) NS2B/NS3 serine protease. The crystallographic structure model of the protease enzyme (PDB code: 2FOM) was used to conduct molecular docking studies of pyrazole-usnic acid derivatives with target proteins. Computational analysis was performed using the Molecular Operating Environment program, Gaussian View software, and ADMETLab platform.
Material and methods:
The inhibitory potential of the derivatives was tested by molecular docking using panduratin A as the positive control, together with density functional theory, molecular electrostatic potential analysis, drug-likeness assessment, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling.
Results:
Among the tested derivatives, compounds 5 and 6 exhibited the most promising inhibitory effects against DENV-2 NS2B/NS3 serine protease. The binding free energy values for these compounds were –7.320 and –7.477 kcal/mol, respectively. These two compounds shared multiple amino acid residues with panduratin A, which was used as a reference inhibitor. Compounds 5 and 6 also displayed negative electrostatic regions surrounding their oxygen atoms, with gap energies of 0.133 and 0.137 eV and dipole moment values of 3.237 and 2.806 D, respectively.
Conclusions:
These computational findings suggest that compounds 5 and 6 may serve as preliminary candidates for dengue virus inhibition. However, further clinical and experimental studies are required to confirm their efficacy and safety.
REFERENCES (39)
1.
Abu-Izneid T, Rauf A, Ahmad Z, Wadood A, Ayub K, Muhammad N, Al-Awthan YS, Maqbool M, Bahattab OS, He- meg HA, et al. 2024. Density functional theory (DFT), molecular docking, and xanthine oxidase inhibitory studies of dinaphthodiospyrol S from Diospyros kaki L. Saudi Pharm J. 32: 101936. https://doi.org/10.1016/j.jsps. 2023.101936.
2.
Araújo AAS, de Melo MGD, Rabelo TK, Nunes PS, San- tos SL, Serafini MR, Santos MRV, Quintans-Júnior LJ, Gelain DP. 2015. Review of the biological properties and toxicity of usnic acid. Nat Prod Res. 29: 2167–2180. https://doi.org/10.1080/147864....
3.
Bazan JF, Fletterick RJ. 1989. Detection of a trypsin-like serine protease domain in flaviviruses and pestviruses. Virology 171: 637–639. https://doi.org/10.1016/0042-6....
4.
Benet LZ, Hosey CM, Ursu O, Oprea TI. 2016. BDDCS, the rule of 5 and drugability. Adv Drug Deliv Rev. 101: 89–98. https://doi.org/10.1016/j.addr....
5.
Bursch M, Mewes JM, Hansen A, Grimme S. 2022. Best-practice DFT protocols for basic molecular computational chemistry. Angew Chem Int Ed. 61: e202205735. https://doi.org/10.1002/anie.2....
6.
Celik S. 2023. DFT investigations and molecular docking as potent inhibitors of SARS-CoV-2 main protease of 4-phenylpyrimidine. J Mol Struct. 1277: 134895. https://doi.org/10.1016/j.mols....
7.
Chambers TJ, Hahn CS, Galler R, Rice CM. 1990. Flavivirus genome organization, expression, and replication. Annu Rev Microbiol. 44: 649–688. https//doi.org/10.1146/annurev. mi.44.100190.003245.
8.
Chambers TJ, Grakoui A, Rice CM. 1991. Processing of the yellow fever virus nonstructural polyprotein: a catalytically active NS3 proteinase domain and NS2B are required for cleavages at dibasic sites. J Virol. 65: 6042–6050. https://doi.org/10.1128/jvi.65....
9.
Croce N, Pitaro M, Gallo V, Antonini G. 2022. Toxicity of usnic acid: a narrative review. J Toxicol. 2022: 8244340. https://doi.org/10.1155/2022/8....
10.
Erbel P, Schiering N, D’Arcy A, Renatus M, Kroemer M, Lim SP, Yin Z, Keller TH, Vasudevan SG, Hommel U. 2006. Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol. 13: 372–373. https://doi.org/10.1038/nsmb10....
11.
Erol M, Celik I, Kuyucuklu G. 2021. Synthesis, molecular docking, molecular dynamics, DFT and antimicrobial activity studies of 5-Substituted-2-(p-Methylphenyl)Benzoxazole derivatives. J Mol Struct. 1234: 130151. https://doi.org/10.1016/j.mols....
12.
Falgout B, Pethel M, Zhang YM, Lai CJ. 1991. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol. 65: 2467–2475. https://doi.org/10.1128/jvi.65....
13.
Filimonov AS, Yarovaya OI, Zaykovskaya AV, Rudometova NB, Shcherbakov DN, Chirkova VY, Baev DS, Borisevich SS, Luzina OA, Pyankov OV, et al. 2022. (+)-Usnic acid and its derivatives as inhibitors of a wide spectrum of SARS-CoV-2 viruses. Viruses 14: 2154. https://doi.org/10.3390/v14102....
14.
Francolini I, Norris P, Piozzi A, Donelli G, Stoodley P. 2004. Usnic acid, a natural antimicrobial agent able to inhibit bacterial biofilm formation on polymer surfaces. Antimicrob Agents Chemother. 48: 4360–4365. https://doi.org/10.1128/AAC.48....
15.
Frimayanti N, Ikhtiarudin I, Septama AW, Susanty A, Isroq ND. 2023. Synthesis, in silico and structural insight of flavonol derivative compounds as new competitive Dengue NS2B/NS3 protease inhibitor. J Res Pharm. 27: 1157–1169. https://doi.org/10.29228/jrp.4....
16.
Frimayanti N, Nasution MR, Etavianti E. 2021. Molecular docking and molecular dynamic simulation of 1,5-benzothiazepine chalcone derivative compounds as potential inhibitors for Zika virus helicase. Jurnal Riset Kimia. 12: 44–52. https://doi.org/10.25077/jrk.v....
17.
Frimayanti N, Yaeghoobi M, Ashrafi SJ, Haghirosadat BF, Octaviani M, Rahmi A. 2024a. Identification of compounds from Zingiber officinale as novel inhibitor for dengue DEN2 NS2B/NS3 serine protease through molecular docking and DFT approaches. Res J Pharm Technol. 17: 795–801. https://doi.org/10.52711/0974-.... 00123.
18.
Frimayanti N, Ikhtiarudin I, Dona R, Oktarizal R, Nurfati- mah AC. 2024b. Exploring substituted tetrazoloquinazoline: biological activities, molecular docking analysis, and anti-breast cancer MCF7/HER2 effects. Adv Pharmacol Pharma Sci. 6952142. https://doi.org/10.1155/2024/6....
19.
Guo L, Shi Q, Fang JL, Mei N, Ali AA, Lewis SM, Lea- key JEA, Frankos VH. 2008. Review of usnic acid and usnea barbata toxicity. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 26: 317–338. https://doi.org/10.1080/105905....
20.
Ipek C, Gümüş H, Şimşek M, Tosun M. 2023. DFT and molecular docking study of 1-(2’-thiophen)-2-propen- 1-one-3-(2,3,5- trichlorophenyl) (TTCP) molecule as antiviral to COVID-19 main protease. Arab J Sci Eng. 48: 1031–1040. https://10.1007/s13369-022-072....
21.
Jia CY, Li JY, Hao GF, Yang GF. 2020. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Dis-cov Today. 25: 248–258. https://doi.org/10.1016/j.drud.... 2019.10.014.
22.
Kavita K, Anjali G, Anujit G, Pinki D, Fahmina Z, Anubha S, Priya V. 2024. In silico identification and validation of phenolic lipids as potential inhibitor against bacterial and viral strains. J Biomol Struct Dyn. 42: 2525–2538. https://doi.org/10.1080/073911....
23.
Kularatne SA, Dalugama C. 2022. Dengue infection: global importance, immunopathology and management. Clin Med (Lond). 22: 9–13. https://doi.org/10.7861/clinme.... 2021-0791.
24.
Kwong SP, Wang C. 2020. Review: usnic acid-induced hepatotoxicity and cell death. Environ Toxicol Pharmacol. 80: 103493. https://doi.org/10.1016/j.etap....
25.
Lessa CLS, Hodel KVS, Gonçalves MS, Machado BAS. 2023. Dengue as a disease threatening global health: a narrative review focusing on Latin America and Brazil. Trop Med Infect Dis. 8: 241. https://doi.org/10.3390/tropic....
26.
Li H, Clum S, You S, Ebner KE, Padmanabhan R. 1999. The serine protease and RNA-stimulated nucleoside triphosphatase and RNA helicase functional domains of dengue virus type 2 NS3 converge within a region of 20 amino acids. J Virol. 73: 3108–3116. https://doi.org/10.1128/jvi.73....
27.
Li J, Lim SP, Beer D, Patel V, Wen D, Tumanut C, et al. 2005. Functional profiling of recombinant NS3 proteases from all four serotypes of dengue virus using tetrapeptide and octapeptide substrate libraries. J Biol Chem. 280: 28766–28774. https://doi.org/10.1074/jbc.M5....
28.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 46: 3–26. https://doi.org/10.1016/s0169-....
29.
Mary YS, Krátký M, Vinsova J, Baraldi C, Gamberini MC. 2021. DFT, molecular docking and SERS (concentration and solvent dependant) investigations of a methylisoxazole derivative with potential antimicrobial activity. J Mol Struct. 1232: 130034. https://doi.org/10.1016/ j.molstruc.2021.130034.
30.
Matta CF, Arabi AA. 2011. Electron-density descriptors as predictors in quantitative structure–activity/property relationships and drug design. Future Med Chem. 3: 969–994. https://doi.org/10.4155/fmc.11....
31.
Nurulita Y, Afriana N, Ikhtiarudin I, Frimayanti N, Jasril J. 2021. Synthesis, docking, and molecular dynamic study of hydrazones compounds to search potential inhibitor for breast cancer MCF-7. TJPS. 45: 447–486. https:// 10.56808/3027-7922.2529.
32.
PaŸdziora W, Podolak I, Grudziñska M, Paœko P, Grabow- ska K, Galanty A. 2023. Critical assessment of the anti- inflammatory potential of usnic acid and its derivatives – a review. Life 13: 1046. https://doi.org/10.3390/life13....
33.
Syahri J, Hilma R, Nurlaili, Sari MK, Frimayanti N, Ali AH, Latip J. 2023. Synthesis, antimalarial activities of secondary amine-substituted eugenol compounds against Plasmodium falciparum and in silico molecular docking analysis. Sains Malays. 52: 3463–3474. http://doi.org/10.17576/jsm-20....
34.
Suzuki T, Kiyotani T, Maeda M, Katayama T, Tomita-Yokotani K, Syafii W, Muladi S. 2011. Furanoditerpenes from Arcangelisia flava (L.) Merr. and their antifungal activity. Phytochem Lett. 4: 333–336. https://doi.org/10.1016/ j.phytol.2011.07.002.
35.
Vallianatou T, Tsopelas F, Tsantili-Kakoulidou A. 2022. Prediction models for brain distribution of drugs based on biomimetic chromatographic data. Molecules 27: 3668. https://doi.org/10.3390/molecu....
36.
Wang H, Xuan M, Huang C, Wang C. 2022. Advances in research on bioactivity, toxicity, metabolism, and pharmacokinetics of usnic acid in vitro and in vivo. Molecules 27: 7469. https://doi.org/10.3390/molecu....
37.
Warrener P, Tamura JK, Collett MS. 1993. RNA-stimulated NTPase activity associated with yellow fever virus NS3 protein expressed in bacteria. J Virol. 67: 989–996. https://doi.org/10.1128/jvi.67....
38.
Wengler G, Wengler G. 1991. The carboxy-terminal part of the NS 3 protein of the West Nile flavivirus can be isolated as a soluble protein after proteolytic cleavage and represents an RNA-stimulated NTPase. Virology 184: 707–715. https://doi.org/10.1016/0042-6....
39.
Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, et al. 2021. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 49: W5–W14. https://doi.org/10.1093/nar/gk....
Share
RELATED ARTICLE
| eISSN: | 2353-9461 |
| ISSN: | 0860-7796 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
