Exploring the Antifungal Activity of 1,4-Naphthoquinone Derivatives through Inhibition of Lanosterol 14-?-Demethylase: An In- Silico Approach

Sumit Raut, Dr. Dinesh Chapale, Neha Mankar, Suraj Chilkawar, Ayush Umare,

doi:10.5281/zenodo.18198978

Research Paper | Open Access
Volume 03 | Issue 01 | Article Id IJPS/250312644

Exploring the Antifungal Activity of 1,4-Naphthoquinone Derivatives through Inhibition of Lanosterol 14-?-Demethylase: An In- Silico Approach
Sumit Raut* Dr. Dinesh Chapale Neha Mankar Suraj Chilkawar Ayush Umare
Priyadarshini J.L. College of Pharmacy, Electronic Zone building, MIDC, Hingna Road Nagpur, Maharashtra, India 441106

Abstract

Fungal infections continue to represent a major global health challenge, especially in immunocompromised populations, and the increasing incidence of antifungal resistance highlights the urgent need for novel therapeutic agents. Lanosterol 14-?-demethylase (CYP51), an essential enzyme involved in fungal ergosterol biosynthesis, is a well-established target for antifungal drug discovery. The present in-silico investigation aimed to assess the antifungal potential of fourteen newly designed 1,4-naphthoquinone derivatives using molecular docking and ADMET prediction approaches. Docking studies were conducted against CYP51 (PDB ID: 4ZDY) to evaluate binding affinity and ligand–protein interactions within the active site. Most of the designed derivatives demonstrated higher binding affinity toward CYP51 than the reference antifungal drug fluconazole, with docking scores observed in the range of ?8.0 to ?9.2 kcal/mol. The docked complexes revealed stable binding characterized by favorable hydrophobic interactions and ?–? stacking with key amino acid residues of the target enzyme. Furthermore, in-silico ADMET analysis indicated that the majority of compounds possessed acceptable drug-likeness and pharmacokinetic properties, including good intestinal absorption, limited blood–brain barrier penetration, and absence of predicted hepatotoxicity and skin sensitization. Although mutagenicity was predicted for some derivatives, several compounds exhibited an overall favorable safety and pharmacokinetic profile. In summary, the findings suggest that these 1,4-naphthoquinone derivatives are promising CYP51 inhibitors and may serve as potential lead molecules for further experimental antifungal evaluation

Keywords

1,4-Naphthoquinone, Lanosterol 14-?-demethylase, Molecular docking, Antifungal activity, AutoDock vina

Introduction

Fungal infections, commonly referred to as mycoses, represent a diverse group of diseases ranging from superficial conditions such as tinea pedis to life-threatening systemic infections. Superficial fungal infections, including dermatophytosis, candidiasis, and Malassezia-associated disorders, are widely distributed across the globe and are particularly prevalent in warm and humid climates [1]. Subcutaneous mycoses primarily result from the traumatic introduction of fungi present in soil or plant material into the skin and underlying tissues, where they generally remain localized but may progress if not properly managed [1]. Systemic fungal infections are categorized as either opportunistic or endemic respiratory mycoses, with endemic forms showing geographical restriction while still affecting both healthy and immunocompromised individuals. The growing incidence of fungal infections and the increasing resistance to existing antifungal drugs highlight the need for the development of new therapeutic agents. Lanosterol 14-α-demethylase (CYP51) plays an essential role in fungal ergosterol biosynthesis and has emerged as one of the most important molecular targets for antifungal therapy. Suppression of this enzyme interferes with cell membrane formation, ultimately leading to fungal cell death. In this context, molecular docking has become a widely used in-silico tool in drug discovery, allowing the prediction of ligand binding modes and affinities within target proteins [2]. Docking algorithms utilize scoring functions to assess receptor–ligand interactions and estimate the thermodynamic stability of protein–ligand complexes [3–5]. This computational approach enables rapid screening of potential bioactive compounds while significantly reducing experimental cost and time [6,7]. Several studies have reported the antifungal potential of 1,4-naphthoquinone derivatives; however, comprehensive in-silico evaluations of their interaction with lanosterol 14-α-demethylase remain insufficient. Therefore, the present study focuses on the molecular docking-based assessment of fourteen 1,4-naphthoquinone derivatives as potential inhibitors of lanosterol 14-α-demethylase. Additionally, ADMET analysis was carried out using SwissADME and pkCSM to identify compounds with favourable pharmacokinetic profiles and suitability for further development as antifungal lead molecules.

MATERIAL AND METHODS:

Platform for molecular docking

All in-silico docking analyses of the 1,4-naphthoquinone (1,4-NQ) derivatives with the target enzyme lanosterol 14-α-demethylase were carried out using the UCSF Chimera software interface. Chimera was employed as the graphical platform to execute individual docking runs using AutoDock Vina, enabling precise protein–ligand interaction evaluation for each derivative [8–10].

Protein Selection and Preparation

The three-dimensional structure of lanosterol 14-α-demethylase (CYP51) used in this study corresponds to the Y140F mutant (PDB ID: 4ZDY) obtained from the Protein Data Bank. This structure was chosen because it represents the fungal lanosterol 14-α-demethylase from Saccharomyces cerevisiae YJM789, making it biologically relevant to antifungal drug discovery. The crystal structure was experimentally determined by X-ray diffraction at a high resolution of 2.02 Å, ensuring detailed and reliable representation of the active site for docking analysis. The PDB file was downloaded and imported into UCSF Chimera, where protein preparation was performed using the Dock Prep module. This process included removal of heteroatoms, addition of hydrogen atoms, and energy optimization to generate a clean and minimized receptor suitable for subsequent molecular docking studies [11].

Ligand preparation

Chemical structures of all derivatives were initially drawn using ChemSketch, and their corresponding SMILES notations were generated. These SMILES strings were imported into Avogadro software using the “Build” function to construct three-dimensional molecular geometries. Geometry optimization of each ligand was performed through energy minimization using a molecular mechanics force field to obtain stable, low-energy conformations suitable for docking analysis. The optimized ligand structures were then saved in PDB format [12]. Each ligand file was subsequently imported into UCSF Chimera and prepared using the Dock Prep module, which included addition of hydrogen atoms and structure refinement, before being stored as finalized ligands for molecular docking.

Molecular Docking

Docking simulations were carried out using lanosterol 14-α-demethylase (PDB ID: 4ZDY) as the receptor and the prepared ligands as inputs. Molecular docking was performed using AutoDock Vina implemented in UCSF Chimera (v1.14) to evaluate binding affinities and interaction profiles [13,14]. A grid box of 60 × 60 × 60 Å was defined to adequately encompass the enzyme active site, with the grid centered at coordinates x = 16.399, y = 11.909, and z = 18.062 Å. Default AutoDock Vina parameters were applied for all docking runs. The resulting docked poses were analysed using the ViewDock panel in UCSF Chimera, and final visualization along with protein–ligand interaction mapping was performed using Discovery Studio Client 2020 [15,16].

ADMET Prediction

To evaluate pharmacokinetic suitability, a systematic ADMET workflow was applied to all 1,4-NQ derivatives. The optimized ligand geometries were saved in SDF format and uploaded to the SwissADME server to determine physicochemical properties, drug-likeness scores, solubility, gastrointestinal absorption, blood–brain barrier permeability, and P-gp substrate predictions. The same SDF files were further analyzed using the pkCSM web server to obtain detailed absorption, metabolism, excretion, and toxicity parameters such as intestinal uptake, skin permeability, CYP interactions, metabolic stability, mutagenicity, hepatotoxicity, and hERG inhibition. Lipinski’s rule-based drug-likeness evaluation was performed across both platforms. This stepwise ADMET analysis enabled early identification of potential pharmacokinetic challenges and toxicity risks prior to in-vitro antifungal validation [17–18].

RESULTS AND DISCUSSION

Molecular docking result

Fluconazole, used as a standard antifungal reference, showed effective binding with the fungal target protein and produced a docking score of −7.6 kcal/mol, forming π alkyl interactions with proline but exhibiting no strong favorable interactions. A series of fourteen synthesized 1,4-naphthoquinone derivatives including D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, and D14 derivatives were evaluated against lanosterol 14-α-demethylase. These compounds demonstrated strong binding affinities with docking scores of −8.6, −9.1, −9.1, −8.5, −8.8, −9.2, −9.0, −8.5, −8.5, −8.0, −8.6, −8.6, −8.8, and −8.9 kcal/mol, respectively. Most derivatives exhibited favorable binding interactions, indicating improved affinity compared to the standard drug fluconazole. These results suggest that structural modification of 1,4-naphthoquinone enhances its ability to interact productively with key amino acid residues of the fungal enzyme, thereby supporting its potential as an antifungal agent [17]

Table No. 1 Docking score of 1,4-NQ derivatives for 4ZDY

Derivatives.	Structure	IUPAC Name of ligand	Binding Energy (kcal/mol)	Interaction
1		2-phenoxynaphthalene-1,4-dionenol	-8.6	Conventional hydrogen, pi alkyl and pi-pi T shaped bonds
2		2-(2-methylphenoxy) naphthalene-1,4-dione	-9.1	_
3		2-(3-methylphenoxy) naphthalene-1,4-dione	-9.1	C-H bond, pi-sulphur, pi-alkyl and pi-pi T shaped bond.
4		2-(2-hydroxyphenoxy) naphthalene-1,4-dione	-8.5	C-H bond, pi-sulphur, pi-alkyl, p—Donor H bond and pi-pi T shaped bond.
5		2-(2-acetylphenoxy) na phthalene-1,4-dione	-8.8	Conventional hydrogen, pi sigma and pi-pi T shaped bonds
6		2-(4-acetylphenoxy) naphthalene-1,4-dione	-9.2	C-H bond, pi alkyl, pi-pi T shaped, pi-Sulphur, pi-pi stacked
7		2-(3-acetylphenoxy) naphthalene-1,4-dione	-9.0	Conventional hydrogen, pi-pi stacked, pi-sigma and pi-alkyl bond
8		2-[(1,4-dioxo-1,4-dihydronaphthalen-2-yl) oxy] benzoic acid	-8.5	C-H bond, pi alkyl and amide-pi stacked bond
9		3-[(1,4-dioxo-1,4-dihydronaphthalen-2-yl) oxy]-4,5-dihydroxybenzoic acid	-8.5	Van der waals, pi alkyl, amide-pi stacked , pi donor, pi sigma bond.
10		4-[(1,4-dioxo-1,4-dihydronaphthalen-2-yl) oxy]-3-methoxybenzoic acid	-8.0	Van der waals, pi alkyl, amide-pi stacked , pi donor, pi sigma bond.
11		2-(2-nitrophenoxy) naphthalene-1,4-dione	-8.6	Van der waals, pi alkyl, amide-pi stacked and pi sigma bond.
12		2-(4-nitrophenoxy) naphthalene-1,4-dione	-8.6	Conventional hydrogen, pi-alkyl, pi sigma, pi-sulphur and pi-pi T shaped bond
13		2-(4-bromophenoxy) naphthalene-1,4-dione	-8.8	Conventional hydrogen, van der waals. pi-alkyl, pi sigma, pi-sulphur, pi-pi T shaped, amide-pi stacked bond.
14		2-(4-iodophenoxy) naphthalene-1,4-dione	-8.9	pi-alkyl, pi sigma, pi-sulphur, pi-pi T shaped bond.
15		2-(2,4-difluorophenyl)-1-(1,2,4-triazin-2(5H)-yl)-3-(1H-1,2,4-triazol-1-yl) propan-2-ol	-7.6	Carbon hydrogen, pi alkyl

Visualization of the docking complexes in BIOVIA Discovery Studio highlighted the crucial role of conventional hydrogen bonds along with hydrophobic interactions such as π–π stacking, π–alkyl, and alkyl contacts in stabilizing ligand binding within the active site of lanosterol 14-α-demethylase. These interactions collectively contribute to effective enzyme inhibition. The optimized docking poses and detailed binding interactions of the selected derivatives (Top 3) are presented in 2D and 3D diagram as Figures 1-3 for D5, D6 and D7 and standard fluconazole in figure 4. Fluconazole show binding inhibition toward amino acid proline (PRO A:238), leucine (LEU A:96), serine (SER A:508 and SER A:382) and glycine (GLY A:73). Synthesized derivatives shows same binding in 3 derivatives D5, D6 and D12 i.e PRO A:238, SER A:382 in D12, SER A:382 in D5 and D12.

2D Diagram 3D Diagram

Figure 1 (D5)

2D Diagram 3D Diagram

Figure 2 (D6)

2D Diagram 3D Diagram

Figure 3 (D12)

2D Diagram 3D Diagram

Figure 4 (Fluconazole)

1. ADMET Result

The drug-likeness capability of can be predicated using Lipinski, Ghose, Veber, Egan, and Muegge rules, which are based on certain physicochemical parameters such as LogP (for oral in range of 1.35 − 1.8, sub-lingual > 5), total polar surface area (tPSA, < 140 Å), number of donors (< 10), and acceptors > 5) [19]. Whereas, aqueous solubility and Blood-Brain Barrier (BBB) values of the ligands preferably lay in the range of − 6.5 to 0.5 and − 3.0 to 1.2, respectively [20, 21]. Moreover, p-glycoprotein (P-gp) non-substrate caused drug resistance [22]. The ADMET analysis of all 1,4-NQ derivatives showed acceptable drug-likeness profiles with no Lipinski rule violations, indicating good oral drugability. As table 2, all compounds exhibited moderate water solubility (logS −3.10 to −4.49) and high intestinal absorption, mostly above 90%, except Derivative 9, which showed lower absorption (56.87%). The tPSA values ranged from 109.68–136.48 Å², supporting good permeability characteristics. Most derivatives showed poor BBB permeation, indicated by negative or low BBB scores, while Derivative 9 showed a positive value (1.086), suggesting the ability to cross the blood–brain barrier. None of the molecules acted as P-gp substrates, suggesting reduced chances of efflux-mediated drug resistance. AMES toxicity results revealed that several derivatives (Der 4, 9, 12, 13, 14) were non-mutagenic, while others showed positive AMES toxicity similar to the reference drug fluconazole. This 14 Derivatives not show hepatotoxicity and skin sensitization except D2 and D8. Overall, the ADMET profile suggests that most derivatives possess good absorption properties, acceptable solubility, and non-violating drug-likeness, with some compounds standing out as safer candidates based on AMES results. [17-19]

Table no. 2

1,4-NQ compound	Water solubility (log mol/L)	tPSA (A²⁾	Intestinal absorbtion (%)	BBB permeation	p-gp substrate	Lipinsiki violation	AMES toxicity	Hepato Toxicity	Skin Sensi- tization
D 1	-3.739	109.68	96.86	0.341	No	0	Yes	No	No
D 2	-3.961	116.054	96.663	0.353	No	0	Yes	Yes	No
D 3	-4.038	116.054	97.58	0.313	No	0	Yes	No	No
D 4	-3.10	114.48	94.39	-0.079	No	0	No	No	No
D 5	-4.125	126.58	96.828	-0.1	No	0	Yes	No	No
D 6	-4.086	126.58	96.931	0.02	No	0	Yes	No	No
D 7	-4.086	126.58	96.931	-0.1	No	0	Yes	No	No
D 8	-3.666	125.010	93.164	-0.245	No	0	Yes	Yes	No
D 9	-3.628	134.599	56.871	1.086	Yes	0	No	No	No
D 10	-3.81	136.489	94.946	-0.59	No	0	Yes	No	No
D 11	-4.49	124.342	94.577	-0.511	No	0	Yes	No	No
D 12	-4.41	124.342	95.105	-0.517	No	0	No	No	No
D 13	-4.455	123.557	95.362	0.296	No	0	No	No	No
D 14	-4.446	128.951	95.997	0.292	No	0	No	No	No
Fluconazole	-3.196	130.145	85.063	-1.114	No	0	Yes	Yes	No

We use Protox software to check toxicity of this derivatives, all derivatives along with standard show class 4 toxicity which means least toxic (High LD50) safer drug. The toxicity evaluation of all fourteen compounds revealed a consistent oral LD?? of 500 mg/kg, placing them in Toxicity Class 4, which indicates moderate acute toxicity. Organ toxicity profiling showed that liver, nervous system, and heart toxicity remained inactive for almost all compounds, suggesting good safety toward these major organs. However, nephrotoxicity and respiratory toxicity repeatedly appeared active in several molecules, indicating a possible kidney and lung toxicity risk across the dataset. Among toxicological endpoints, mutagenicity appeared active for multiple compounds, while carcinogenicity and immunotoxicity remained mostly inactive, with only rare borderline activity. Cytotoxicity predictions were generally inactive, confirming low cell-level toxicity. Almost all compounds were predicted to be BBB-active, showing their ability to cross the blood–brain barrier. Molecular initiating event prediction showed strong and consistent activation of transthyretin (TTR) binding, while all hormonal receptors (AR, ER, PPAR-γ) were consistently inactive, indicating no endocrine-related toxicity. Stress-response pathways such as ARE, HSE, ATAD5, and p53 were largely inactive, with occasional mild mitochondrial membrane potential disturbance in a few structures. Metabolism-related toxicity showed that CYP2C9 inhibition was the only repeatedly active finding, while all other CYP enzymes were mostly inactive. Overall, the combined toxicity profile indicates that the compounds exhibit moderate oral toxicity, low hepatotoxic/neurotoxic cardiotoxic risk, consistent TTR binding, and low endocrine toxicity, but attention is required due to predicted mutagenicity and recurrent nephrotoxicity/respiratory toxicity in several molecules. [23-26].

DISCUSSIONS

The docking results indicate that the 1,4-naphthoquinone derivatives possess significant affinity toward lanosterol 14-α-demethylase, suggesting strong antifungal potential. Most of the derivatives exhibited stronger binding affinities than fluconazole, which may be attributed to the presence of phenoxy, halogen, hydroxyl, and acetyl substituents that enhance π–π interactions and stabilize hydrogen bonding within the enzyme’s active site. The ADMET analysis further supported these findings, demonstrating high intestinal absorption, acceptable aqueous solubility, and overall favourable drug-likeness profiles. The absence of Lipinski rule violations highlights their suitability for oral administration. Although some derivatives showed AMES positivity or predicted nephrotoxicity and respiratory toxicity, these risks are comparable to those of standard antifungal agents and may be mitigated through further structural optimization. The consistent TTR-binding prediction suggests a common molecular initiation pathway among all derivatives. Collectively, the docking, physicochemical, and toxicity results indicate that several derivatives, particularly those bearing halogen or acetyl substitutions, possess the structural features required for effective CYP51 inhibition. These findings are consistent with previously reported antifungal mechanisms of quinone-based scaffolds and warrant further in vitro and in vivo validation.

CONCLUSIONS

The present in-silico investigation demonstrates that the synthesized 1,4-naphthoquinone derivatives possess strong potential as novel antifungal candidates targeting lanosterol 14-α-demethylase. Most derivatives exhibited higher binding affinity than the standard drug fluconazole, highlighting the importance of phenoxy, halogen, hydroxyl, and acetyl substitutions in strengthening protein–ligand interactions. Detailed analysis of docking poses revealed stable binding through hydrogen bonding, π–π stacking, and hydrophobic interactions, confirming the ability of these derivatives to effectively fit within the active site of CYP51. ADMET predictions further reinforced their suitability as drug-like molecules, with high intestinal absorption, good solubility range, no Lipinski rule violations, and minimal P-gp substrate involvement, suggesting favorable oral bioavailability. Toxicity assessment classified all compounds under Class 4, indicating moderate but acceptable acute toxicity along with low risks of hepatotoxicity, neurotoxicity, and cardiotoxicity. Although certain molecules showed predicted nephrotoxicity, respiratory toxicity, or mutagenicity, these concerns can be addressed with structural optimization in future studies. All 14 derivatives not show any hepatotoxicity and skin sensitization except D2 and D8 which show liver toxicity. Overall, the combined docking, drug-likeness, and toxicity data clearly support that several of the investigated derivatives particularly halogenated and acetophenone analogues represent promising scaffolds for antifungal drug development. These findings provide a strong computational foundation for further experimental validation through in-vitro assays, mechanistic studies, and in-vivo evaluations to advance these molecules toward safer and more effective antifungal therapy.

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