Molecular Investigation of Dual Antifungal and Antibacterial Activities by Aloe Vera in Vulvovaginal Infection: An In Silico Approach

Nurul Jannatul Wahidah¹*, Revi Gama Hatta Novika¹, Siti Nurhidayati¹, Atriany Nilam Sari¹, Rufidah Maulina¹, Luluk Fajria Maulida¹, Gabriella Chandrakirana Krisnamurti²,

Khim Yatul Nguzum², Lanjar Sumarno³

¹Midwifery Study Program, Medical Faculty, Sebelas Maret University Surakarta, Indonesia.

²Graduate Program of Bioscience, Faculty of Mathematics and Natural Sciences,

Sebelas Maret University Surakarta, Indonesia.

³Research Center for Agroindustry, National Research and Innovation Agency, Bogor, West Java, Indonesia.

*Corresponding Author E-mail: njwahidah@staff.uns.ac.id

ABSTRACT:

Females in their reproductive age are the most susceptible to vulvovaginal infection. The infection is dominated by vulvovaginal candidiasis (VVC) and often exacerbated with bacterial vaginosis (BV). The imbalance microbiome composition which is dominated by Candida albicans, followed by adverse effects of antibiotics may increase the severity of infection. Natural bioactive compounds, particularly from Aloe vera, are potentially to develop as dual antifungal and antibacterial agents with less adverse effect and broad-spectrum activity. The aim of this study is to examine the antifungal and antibacterial activities of A. vera bioactive compounds with in silico. Eleven constituents were predicted for antiinfective, antifungal, and antibacterial activity with PASS Way2Drug. The activities were further evaluated by molecular docking against β-(1,3)-glucan synthase (A0A1D8PCT0_CANAL), glycosyl hydrolase (A0A367YKV9_9ASCO), lanosterol 14-α demethylase (5FSA), and dihydropteroate synthase (1AJ0) using AutoDock Vina. The most potential constituents were identified for drug-likeness and ADME/T. Bioactive compounds proposed as the most potential if they had high PASS score and performed binding to protein with lower binding energy than control. This study found that 5-p-cis-coumaroylquinic acid, trans-5-O-Caffeoylquinic acid, aloe emodin glucoside, and aloe emodin posed efficient binding against β-(1,3)-glucan synthase, glycosyl hydrolase, lanosterol 14-α demethylase, and dihydropteroate synthase, respectively. Though constituents potentially exhibit therapeutic effects, constituents showed less violation of Lipinski rule and toxicity. Further optimization of chemical structure and dose should be applied if bioactive compounds would be administered as a drug.

KEYWORDS: Aloe vera, Antibacterial, Antifungal, Infection, Vulvovaginal.

INTRODUCTION:

Vulvovaginal infection by fungus, namely vulvovaginal candidiasis (VVC) is a common mucosal infection widely occurring in approximately 75% of females especially in their reproductive year¹^,²^,³. Most of the VVC cases are prevalently caused by Candida albicans, more than 50% cases, and non-albicans Candida species, around 40% cases, which colonize the vaginal lumen⁴^,⁵. Fungus C. albicans normally lives in the human host, but abundant invasion causes imbalance of microbiome composition indicated by the loss of protective Lactobacillus species⁶. C. albicans is a commensal organism, but under immunocompromised conditions, it can penetrate host tissues through adhesion, colonization, and invasion stages⁷. It exhibit virulence factors, notably dimorphism, characterized by its ability to shift from yeast to hyphal fungus form under favorable conditions². Besides fungal, pathogenic bacteria also accompanied the vulvovaginal infection, namely bacterial vaginosis (BV), contributing to massive loss of Lactobacillus species⁸. The virulent Gardnerella spp. Bacteroides spp. Mobiluncus spp., Prevotella spp., Clostridiale spp., and Zozaya spp. are identified as the pathogenic bacteria involved in BV. Invasion of pathogenic bacteria is crucial to the resistance of probiotic therapy in BV⁹.

Antimicrobial medications, such as fluconazole, lincosamide, metronidazole, which are commonly used to treat vulvovaginal infection are commonly used to treat vulvovaginal infection administered both topical and systemic routes⁹. However, the rise of drug resistant strains has become a growing concern¹⁰. Remarkably, antibiotics allow the proliferation of commensal yeast. Hypotheses suggest that the overgrowth of Candida is a consequence from antibiotics lysing resident bacteria, releasing unknown components that trigger yeast virulence factors¹¹. Thus, it is an urge to explore alternative treatment and therapy for vulvovaginal infection, using natural sources¹². One such promising candidate is Aloe vera, which has gained significant attention due to extensive medicinal properties, particularly its antifungal and antibacterial effects¹³^,¹⁴^,¹⁵. The plant's bioactive compounds, including aloin, aloe emodin, and chlorogenic acid contribute to its efficacy against various pathogens, making it a valuable alternative to synthetic antibiotics¹⁶. While traditionally used, the biological activity of its constituents at the molecular level has yet to be fully elucidated

With advancements in computer-based tools, in silico methods now offer a faster and more efficient way to predict how compounds might interact with specific proteins of microbes. Techniques such as molecular docking can simulate these interactions and provide insights into a compound’s potential activity before moving on to laboratory or clinical testing¹⁷^,¹⁸. The efficiency of the docking process improves when the binding site location is identified in advance¹⁹. Using in silico tools, we predicted the biological activity related to antifungal and antibacterial, also analyzed the interaction with key fungal and bacterial proteins including β-(1,3)-glucan synthase, glycosyl hydrolase, lanosterol 14α-demethylase (ERG11), and dihydropteroate synthase (DHPS). This study aims to examine the antifungal and antibacterial potency in bioactive compounds of A. vera with in silico approach, thus providing new insight to the role of A. vera constituents in combating vulvovaginal infection.

MATERIALS AND METHOD:

Biological activity prediction:

A total of eleven bioactive compounds of A. vera (Table 1) identified by HPLC-MS/MS²⁰. The SMILES of each bioactive compound (https://pubchem.ncbi.nlm.nih.gov/) was loaded to the PASS prediction tool (https://www.way2drug.com/PassOnline/), focusing on antifungal, anti-infective, and antibacterial properties.

Protein modeling:

Three-dimensional (3D) structures of Candida spp. (antifungal) target proteins which were not available in crystal form were modeled computationally from their amino acid sequences obtained from Uniprot: Those are β-(1,3)-glucan synthase (A0A1D8PCT0_CANAL) and glycosyl hydrolase (A0A367YKV9_9ASCO). In addition, two other target proteins with available crystal structures were downloaded directly from the Protein Data bank (PDB), those are lanosterol 14-α demethylase (5FSA) and dihydropteroate synthase (1AJ0).

Molecular Docking:

Proteins were prepared by adding charge and removing attached ligands and water molecules using ChimeraX 1.9. Ligands were prepared by minimizing energy and converting into PDB files using PyRx 0.8. Molecular docking was performed using AutoDock Vina integrated in PyRx²¹. The 2D and 3D interactions were visualized and analyzed by Discovery Studio 2024.

Drug-likeness and ADME/T prediction:

Bioactive compounds exhibiting strong predicted activity and favorable molecular interactions were subsequently evaluated for their drug-likeness based on Lipinski’s rule and ADME/T through ADMETSAR 3.0 (https://lmmd.ecust.edu.cn/admetsar3/).

RESULTS AND DISCUSSION:

Screening of antifungal and antibacterial activity of Aloe vera bioactive compounds:

Figure 1 showed the eleven bioactive compounds from A. vera extracts that averagely have moderate to high antifungal activity and moderate to low antibacterial activity. Significant biological activity represented by Pa>0.7 in PASS prediction, suggesting the potential activity desirable for further analysis. The Pa value in the range of 0.5 - 0.7 suggested moderate activity, while Pa<0.5 may indicate less activity¹⁸. Constituents showing potent antiinfective activity was only aloe emodin glucoside, thus this study decided to focus on constituents with moderate to high antifungal and antibacterial activities. Based on the prediction, all bioactive compounds in the prediction, except aloe emodin, showed moderate to high antifungal activity. The antibacterial activity predicted exhibited by aloesin, aloe emodin glucoside, 5-p-cis-Coumaroylquinic acid, 5-p-trans-Coumaroylquinic acid, chlorogenic acid, and trans-5-O-Caffeoylquinic acid. Aloe emodin glucoside was predicted to exhibit high anti-infective, antifungal, and antibacterial activity. Biological activity prediction would further be confirmed with a binding affinity score.

Figure 1. Virtual prediction of biological activity from A.vera bioactive compounds focusing on anti-infective, antifungal, and antibacterial

Binding affinity of Aloe vera bioactive compounds to antifungal and antibacterial protein:

The binding affinity of A. vera bioactive compounds toward the respective protein was further identified and compared with the commercial inhibitors as the control (Table 1). Binding affinity of the complex ligand and protein purposed to determine the strength and susceptibility of ligand to bind with the protein. Ligand is determined to potentially interact with the protein if the binding energy is lower than control¹⁸^,²². Among the tested bioactive compounds, 5-p-trans-Coumaroylquinic acid showed the strongest predicted inhibition of β-(1,3)-glucan synthase (-7 kcal/mol), trans-5-O-Caffeoylquinic acid most effectively inhibited glycosyl hydrolase (-7.3 kcal/mol), and aloe emodin glucoside significantly inhibited Lanosterol 14-α demethylase (-9.6 kcal/mol), although with a weaker affinity than the control. In the antibacterial activity, aloe emodin (-6.7 kcal/mol) performed the strongest inhibition against DHPS. The bioactive compounds with higher binding energy than control were considered potential and used for further analysis.

Table 1. Binding energy score of ligands toward antifungal and antibacterial receptors

Receptor	PubChem ID	Binding energy (kcal/mol)
Receptor	PubChem ID	β-(1,3)-glucan synthase	Glycosyl hydrolase	Lanosterol 14-α demethylase (ERG11)	Dihydropteroate synthase (DHPS)
Fluconazole (C)	CID3365	-5	-	-	-
Imidazole-Derived Cellobiose (C)	CID657137	-	-5.6	-	-
Posaconazole (C)	CID468595	-	-	-11.3	-
Sulfanilamide (C)	CID5333	-	-	-	-4.9
Aloe emodin	CID10207	-5.5	-6.3	-8.1	-6.7
Aloin A	CID12305761	-4.7	2.4	-7.6	-5.8
Aloin B	CID14989	-5.1	-2.8	-7.5	-2.8
Aloesin	CID160190	-5.3	-4.9	-7.7	-1.6
Aloe emodin glucoside	CID147295	-5.4	-5.2	-9.6	4
Chlorogenic acid	CID1794427	-5.4	-6.5	-8.4	-4.8
trans-5-O-Caffeoylquinic acid	CID5280633	-5	-7.3	-8.1	-4.7
5-p-cis-Coumaroylquinic acid	CID90478782	-5.6	-7.1	-7.9	-5.1
5-p-trans-Coumaroylquinic acid	CID164893	-7	-7.2	-7.6	-4.5
8-O-Methyl-7-hydroxyaloin A	CID101713462	-4.8	10.8	-8	-3.6
8-O-Methyl-7-hydroxyaloin B	CID101713463	-4.6	2.1	-7.8	-2.9

Table 2. Amino acid residues involved in the interactions of antifungal proteins with ligands from A. vera

Protein	Ligand	Interaction
Protein	Ligand	Hydrogen	Hydrophobic	Others
β-(1,3)-glucan synthase	FCZ	-	MET467, CYS498, PHE572, VAL576, TYR639	MET467
	Aloe emodin	TYR471	TYR471, CYS498	-
	Aloin B	MET467	MET467, TYR468, TYR471	-
	Aloesin	MET467	TYR471, TYR639	-
	Aloe emodin glucoside	TYR471	TYR471, MET467, PHE572, VAL576	-
	Chlorogenic acid	TYR471, TYR639, ARG647	TYR468, TYR471	-
	5-p-cis-Coumaroylquinic acid	MET467	TYR471	-
	5-p-trans-Coumaroylquinic acid	TYR468	-	-
Glycosyl hydrolase	IDC	GLU253, GLU539, TRP581, GLU598	VAL445	-
	Aloe emodin	MET477	VAL445, LEU446, LEU476, TYR471	-
	Chlorogenic acid	ASN255, GLU539, TRP581	TRP180, TYR471, TRP581	GLU539
	trans-5-O-Caffeoylquinic acid	VAL445, GLU539	TRP180, TYR471	-
	5-p-cis-Coumaroylquinic acid	GLU253, VAL445, GLU598	TRP180, TYR471	-
	5-p-trans-Coumaroylquinic acid	GLU539	TRP180, TYR471, TRP581, PHE600	-
ERG11	PCZ	ALA61, GLY65, SER378, HIS468, SER507	TYR64, ALA61, LEU88, TYR118, LEU121, PRO230, PHE233, GLY307, LEU376, HIS377, MET508	ILE304
	Aloe emodin	HIS377, TYR505, SER507	TYR64, PRO230, PHE233	-
	Aloe emodin glucoside	TYR118, SER378	LEU121, PHE233, LEU376	MET508
	Chlorogenic acid	TYR132, ARG381, SER507	LEU376, HIS377	MET508
	trans-5-O-Caffeoylquinic acid	HIS377, SER378, ARG381	LEU376, HIS377	-
	8-O-Methyl-7-hydroxyaloin A	TYR132, GLY307, HIS468, CYS470	TYR118, LEU376	MET508

Five A. vera bioactive compounds, aloe emodin, chlorogenic acid, trans-5-O-Caffeoylquinic acid, 5-p-cis-Coumaroylquinic acid, and 5-p-trans-Coumaroylquinic acid, were chosen as the inhibitor candidate for glycosyl hydrolase. Glycosyl hydrolase is an enzyme responsible for hydrolysis of the glycosidic bonds of carbohydrate and polysaccharides³¹^,³². Molecular docking study showed that chlorogenic acid, trans-5-O-Caffeoylquinic acid, 5-p-cis-Coumaroylquinic acid, and 5-p-trans-Coumaroylquinic acid posed similar binding as control ligand in inhibiting glycosyl hydrolase (Figure 2B). The IDC is a potent antifungal drug azole class which serves as a key pharmacodynamic fragment for antifungal activity³³. The amino acid residues comprising the binding were Glu253, Val445, Glu539, Trp581, and Glu598. Inhibition of glycosyl hydrolase may disrupt fungal cell wall synthesis and remodelling, as well as biofilm formation. The loss of structural integrity of the fungal cell wall can weaken the wall, leading to fungal death²⁴. It indicates that chlorogenic acid, trans-5-O-Caffeoylquinic acid, 5-p-cis-Coumaroylquinic acid, and 5-p-trans-Coumaroylquinic acid performed inhibition activity against glycosyl hydrolase in a similar manner as IDC.

The antifungal activity of A. vera bioactive compounds was further evaluated against ERG11, an enzyme which is highly conserved in fungi. It essentially converts lanosterol to ergosterol in fungal cell wall formation ³⁴. It becomes the main target of azole drug through blocking sterol biosynthesis, thus the enzyme fails to produce ergosterol. Ergosterol is structurally similar to cholesterol in mammalian hosts, however, it cannot be replaced by cholesterol in fungal cells³⁵ . A. vera bioactive compounds, aloe emodin, aloe emodin glucoside, chlorogenic acid, trans 5-O-caffeoylquinic acid, and 8-O-methyl-7-hydroxyaloin A, was potentially inhibit lanosterol 14-α demethylase in the posaconazole and lanosterol 14α-demethylase binding site (Figure 2C). Showing His337, Ser507, Phe233, Pro230, Tyr118, Ser378, Leu376, Met508, Leu121, Leu376, His468, Glu307 amino acid residues which predominantly formed binding site of A. vera bioactive compounds to the enzyme. Based on the prescribed criteria for the most potent bioactive compounds, 5-p-cis-coumaroylquinic acid, trans-5-O-Caffeoylquinic acid, and aloe emodin glucoside demonstrated highly efficient inhibition against β-(1,3)-glucan synthase, glycosyl hydrolase, and ERG11, respectively. These compounds exhibited the lowest binding energies within the inhibitory sites of the enzymes and achieved high antifungal PASS score.

Antibacterial activity of Aloe vera bioactive compounds:

Vulvovaginal candidiasis is a common vulvovaginal infection which is sometimes accompanied by bacterial vaginosis (BV), presenting simultaneous characteristics. Differently from VVC, BV involved a wide spectrum of anaerobic and facultative bacteria species. It involves Mobiluncus spp., Fannyhessea vaginae, multiple G. vaginalis species, Clostridiale spp., Prevotella spp., and others³⁶^,⁹ . The evidence of BV showed that virulent Gardnerella spp. also possibly could be a key factor in BV pathogenesis⁸. The pathogenic bacteria invade vaginal epithelial cells, altering vaginal Lactobacillus spp⁶. This study evaluated the antibacterial activity of A. vera extract in BV through interfering bacterial folate synthesis pathway. The dihydropteroate synthase (DHPS) is the key enzyme by catalyzing condensation of 6-hydroxymethyl-7,8–dihydropterin-pyrophosphate (DHPP) with p-aminobenzoic acid (pABA). This mechanism allows folic acid and amino acid synthesis, thus inhibiting DHPS may lead to bacterial death³⁷. Aloe emodin, aloin A, and 5-p-cis-coumaroylquinic acid were chosen as the potent antibacterial agents (Table 3). Showing that A. vera bioactive compounds exhibit DHPS inhibition similarly as sulfanilamide through Arg63, Thr62, His257, Lys221, Arg255, and His257 residues (Figure 3). Aloe emodin was potentially showing antibacterial activity through inhibiting DHPS.

Figure 3. Molecular interaction of aloe emodin (blue), aloin A (turquoise), 5-p-cis-Coumaroylquinic acid (yellow) from A. vera and control compounds (pink) against DHPS.

Drug-likeness and ADME/T of A. vera bioactive compounds:

Four bioactive compounds which showed the most potential in the molecular docking study were employed for drug-likeness and ADME/T prediction (Table 4). As a topical and oral drug which targets fungal and bacterial infection, bioactive compounds should exhibit low Lipinski violation, optimum membrane adsorption, low blood brain barrier, and no risk of toxicity. Aloe emodin, 5-p-cis-coumaroylquinic acid, and trans-5-O-caffeoylquinic acid conformed to Lipinski's Rule of Five, signifying their high drug-likeness. Moreover, aloe emodin exhibited the most satisfying lipophilicity (logP) and human intestinal adsorption among all constituents. The bioactive compounds may perform favorable distribution, represented by high plasma protein binding. However, aloe emodin and aloe emodin glucoside were found to have a high risk of mutagenicity and carcinogenicity. Both 5-p-cis-coumaroylquinic acid and trans-5-O-caffeoylquinic acid were high in blood brain barrier, indicating that constituents easily cross the BBB and were favorable as neuroactive drugs³⁸. It is unnecessary for topical drugs to have high BBB penetration as it may lead to unwanted systemic side effects³⁰. Compared to other constituents, aloe emodin showed the most potential, though it may become a mutagenic and carcinogenic agent. Generally, those four constituents showed less favorable to serve as a drug without structural modification or dose alteration. Modification may optimize drug bioavailability and safety.

CONCLUSION:

Bioactive compounds of A. vera potentially treat vulvovaginal infection by inhibiting proteins involved in fungal cell wall synthesis and bacterial folate biosynthesis. The treatment of VVC mainly exhibited by 5-p-cis-coumaroylquinic acid, trans-5-O-caffeoylquinic acid, and aloe emodin glucoside which are susceptible to interact with β-(1,3)-glucan synthase, glycosyl hydrolase, and ERG11, respectively. Treatment of BV exhibited via DHPS inhibition in folate biosynthesis by aloe emodin. Bioactive compounds also possible to be developed as therapeutic drug with structure and dose optimization.

ACKNOWLEDGEMENT:

The authors would like to express their sincere gratitude to the Institute for Research and Community Service (LPPPM) of Universitas Sebelas Maret (UNS) for the financial support provided through the research grant under contract number 371/UN27.22/PT.01.03/2025. This support has significantly contributed to the successful completion of this study.

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Received on 15.07.2025 Revised on 14.11.2025

Accepted on 11.01.2026 Published on 01.07.2026

Available online from July 04, 2026

Research J. Pharmacy and Technology. 2026;19(7):3212-3218.

DOI: 10.52711/0974-360X.2026.00457

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Compounds	Molecular weight (g/mol)	logP	Lipinski violation	HBA	HBD	HIA	PPB	BBB	AMES mutagenicity	Carcinogenicity
Aloe emodin	270.24	2.42	0	5	3	93.9%	94.9%	21.7%	+	+
Aloe emodin glucoside	432.38	0.72	1	10	6	81%	82.5%	7.6%	+	+
5-p-cis-Coumaroylquinic acid	338.31	0.04	0	8	5	65.3%	42.4%	65%	-	-
trans-5-O-Caffeoylquinic acid	338.31	0.04	0	8	5	54.7%	46%	49.9%	-	-

Protein	Ligand	Hydrogen	Hydrophobic
DHPS	Sulfanilamide	THR62, ARG63, SER219, ARG255, HIS257	ARG63, LYS221, HIS257
	Aloe emodin	THR62, ARG63, HIS257	ARG63, PHE190, ARG220, LYS221, PRO232
	Aloin A	THR62, ARG63, PRO64	ARG63, PRO64, LYS221
	5-p-cis-Coumaroylquinic acid	LYS221, ARG255, HIS257	ARG63, ARG220, LYS221