Abstract
Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole’s potency to disrupt the homeostasis of glucocerebrosidase (−7.9 kcal/mol) and parkin (−5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.
Keywords: hexaconazole, glucocerebrosidase, parkin, agricultural fungicide, environmental exposure, computation toxicology
Introduction
Parkinson’s disease has been designated as a neurological ailment. People of Hispanic ethnic background have the highest incidence of the disease in the US, followed by non-Hispanic whites, Asians, and blacks. Environmental exposures are among the risk factors for Parkinson’s disease.1 Pesticide exposure, prior head injury, residing in a rural area, using β-blockers, working as an agricultural worker, and drinking well water were the factors that increased the risk of Parkinson’s disease. It has been reported that individuals engaged in agricultural occupations may be exposed to many chemicals, including fungicides.2,3
Toxicological studies revealed that occupational exposure to carbamates, organochlorines, and organophosphates can cause serious damages to the nervous system and contribute to the development of Parkinson’s disease.4,5 These environmental exposures induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillation, and neuronal cell loss, which have long been implicated in the pathophysiologic mechanisms underlying Parkinson’s disease. Recently, several articles, including prospective cohort studies, have been published to examine the association between pesticide exposure and Parkinson’s disease risk. The results of a previous fifteen-year meta-analysis indicated exposure to pesticides was a risk factor for developing Parkinson’s disease.6,7
The contribution of genetics to Parkinson’s disease is suggested by the increased risk of disease associated with a family history of Parkinson’s disease or tremor.8 The greatest genetic risk factor for developing Parkinson’s disease is a mutation in glucocerebrosidase (GBA) which encodes β-glucocerebrosidase, the lysosomal enzyme deficient in Gaucher disease.9 Results of a large multicenter study on 39 patients with Parkinson’s disease and an equal number of matched controls showed an odds ratio greater than 5 for any GBA mutation in Parkinson’s disease patients versus controls.10 In addition, mutations in parkin protein are one of the most commonly known genetic causes of the early onset of Parkinson disease.11 Parkin-mutant Parkinson’s disease could also involve the loss of nor-adrenergic neurons in the locus coeruleus alongside the hallmark degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and its symptoms resemble those of idiopathic PD, with patients presenting with resting tremors, postural instability and bradykinesia. 11–13 However, advances in genomics and bioinformatics have uncovered additional genetic risk factors for Parkinson’s disease. This study explores how environmental exposure of hexaconazole could be a reason for the development of Parkinson’s disease.
Methods
Molecular interaction analyses and molecular dynamics simulation
From the protein data library, the main glucocerebrosidase (protein bank ID; 1OGS) and parkin (protein bank ID; 4I1F) receptors were obtained, and hexaconazole was redocked with glucocerebrosidase receptors.14,15 Simple point charge (SPC) water molecules were used to dissolve hexaconazole, and counter ions (Cl¯ or Na+) were added to neutralize the protein.16,17 The glucocerebrosidase receptors and hexaconazole system were then put through two steps of equilibration for 1,000 ps. The first stage was an ensemble of particles, volume, and temperature (NVT) that transmitted exothermic and endothermic activities to the thermostat. The second phase used a constant NPT (particle number, pressure, and temperature). The NVT, NPT, simulation ensemble, and molecules have been solvated into the aqueous environment at 310 K, which corresponds to the temperature of a human body. The Linear Constraint Solver (LINCS) technique was subsequently used to restrict covalent bonding. In addition, hexaconazole was employed to create the topology of the hormone receptor using the CHARMM 36 force field. To assess the stability of each system, MD was conducted for 10 ns. This study examined the behavior of glucocerebrosidase receptors with hexaconazole during the simulation using root-mean-square calculation (RMSF), root-mean-square deviation (RMSD), radius of gyration (RG), solvent accessible surface area (SASA), and interaction energy calculations. These molecular dynamics simulations included hydrogen bond estimates to support the findings. GROMACS version 2021.4 was used for all evaluations. In order to forecast the important motions in the trajectory, principal component analysis was also carried out. Principal component analysis (PCA) or essential dynamics (ED) is a reliable approach for identifying protein conformations and massive coordinated pattern fluctuations during MD runs.18
Interaction energy of glucocerebrosidase and parkin receptors with hexaconazole
To gage the strength of the interaction between the ligand hexaconazole and glucocerebrosidase receptors, parkin receptors, the non-bonded interaction energy between the ligand and substrate was calculated using GROMACS Coulombic interaction energy and the short-range Lennard- Jones energy.19–22
Analysis of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)
MM-PBSA calculated the binding free energy analysis in accordance with protocol. Hexaconazole’s binding free energy analysis for glucocerebrosidase receptors was calculated. In addition, the van der Waals, solvation, and electrostatic energies were calculated for hexaconazole. The binding free energy was calculated as follows:
 |
Where ΔG is Glucocerebrosidase receptors binding free energy; G Protein represents glucocerebrosidase receptors; G Ligand represents hexaconazole.23
Analyses of density functional theory
The density functional theory (DFT)-based quantum mechanical approach is often used to evaluate the chemical reactivity of compounds in a wide range of applications. This approach is based on precise geometry, electrical properties and spin state. The charge-transfer interactions with the protein binding site are also explained by DFT. The Lee-Yang-Parr correlation function (B3LYP) and Orca 5.2 software were used to analyze charge-transfer with hexaconazole and chlorpyrifos in order to better comprehend it. Avogadro software was used to represent the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO).24
ADME (absorption, distribution, metabolism, and excretion) analyses
The ADME properties of hexaconazole were predicted using the Swiss ADME server. Hexaconazole showed noteworthy results for a few traits. It might disrupt glucocerebrosidase homeostasis, which could be a reason for Parkinson’s pathogenesis.25
Results
Molecular interaction analyses of glucocerebrosidase receptors, parkin receptors with hexaconazole
Molecular docking analyses were performed for glucocerebrosidase and parkin receptors. Disruption in the homeostatic function of glucocerebrosidase and parkin may lead to Parkinson; it could be due to environmental exposure as it has been reported that gene-environment interactions are understood to be the underlying cause of idiopathic Parkinson’s disease. Molecular docking of glucocerebrosidase and parkin receptors with hexaconazole revealed that the β-glucocerebrosidase receptor interacts with residues SER 25 and ARG 2, which are stabilized with hydrogen bonds, while residues CYS 16, TYR 418, PRO 3, and MET 49 were associated with Alkyl and Pi-Alkyl, the binding energy of hexaconazole and glucocerebrosidase was (−7.9 kcal/mol). In addition, PHE 26 and ASP 24 were associated with Pi-Pi stacked and Pi-anion, respectively. The residues CYS 4 and ARG were also associated with the carbon-hydrogen bond (Fig. 1). The molecular interaction of hexaconazole with parkin revealed that parkin interacts with residue GLY 152 as hydrogen bond and resides PRO 153, 223, HIS 215, LYS 151, CYS 212, and LYS 211, which are stabilized with Alkyl and Pi-Alkyl bond Fig. 2. The hexaconazole binding energy with parkin was found to be (−5.67 kcal/mol). The details of molecular interaction are given in Table 1.
Fig. 1.
Molecular interaction analyses of β-Glucocerebrosidase with hexaconazole.
Fig. 2.
Molecular interaction analyses of parkin with hexaconazole.
Table 1.
Details of molecular interaction of 1OGS and parkin 411f with hexaconazole.
| Ligand | Amino acid residues involved in hydrogen bonds | Docking final intermolecular energy (ΔG) = vdW+ Hbond + desolv Energy (kcal/mol) | Inhibition constant (Ki) |
|---|---|---|---|
| Glucocerebrosidase receptors+ hexaconazole | 2 ARG 25 SER |
−10.04 | 1.63 uM |
| Parkin receptors+ hexaconazole | 152 GLY | −5.67 | 69.31 uM |
Molecular dynamics simulation of glucocerebrosidase receptors, parkin receptors with hexaconazole
The RMSD of glucocerebrosidase receptors with hexaconazole revealed that complexes acquired equilibrium at 0.1 nm at 10 ns range (0.1 nm to 0.1 nm), whereas parkin receptors with hexaconazole revealed that complexes attained equilibrium at 0.5 nm (0.2 to 0.5 nm). The results showed that complexes were stable during the MD simulations, with fewer fluctuations and better stability (Fig 3A). The results of RMSF analysis represents that all complexes were stable in same pattern during MD simulations, with fewer fluctuations and better stability (Fig. 3B). The gyration findings for 1OGS with hexaconazole fluctuated at 2.3 nm and decreased to 2.4 nm during MD simulation, and 4I1F with hexaconazole fluctuated at 2.5 nm and decreased to 2.4 nm during MD simulation (Fig. 3C).
Fig. 3.
MD simulation analysis of glucocerebrosidase and parkin receptors with Hexaconazole. A) RMSD B) RMSF C) radius of gyration D) hydrogen bond E) SASA Glucocerebrosidase with hexaconazole orange color. Parkin with hexaconazole red color.
In addition, it is already known that hydrogen bonds play an important role in the assessment of stability complexes. The findings reveal that hexaconazole has the ability to form hydrogen bonds with parkin and glucocerebrosidase receptors. After 10 ns the number of hydrogen was observed is depicted in Fig. 3D. The solvent-accessible surface area, or SASA, is a measure of how well enzyme and ligand complexes interact with solvents. The SASA also predicts the conformational changes that occur during the time of interactions. The SASA values for 1OGS- hexaconazole and 4I1F-hexaconazole were in the range of 30 nm and 50 nm, respectively. In addition, principal component analysis was performed to predict the significant motions in the MD trajectory. PCA predicts the binding of the substrate in the complexes. The motion captured by eigenvectors was 88% for hexaconazole 1OGS (Fig. 4A and B), and 92% for hexaconazole 4I1F (Fig. 4C and D). In the graph, each dot stands for one complex confirmation and shows variation in conformational distributions. The details of stability analyses are given in Table 2 and detailed set-up of MD simulations for each complex are provided in supplementary Table 1.
Fig. 4.
Principal component analysis; A, B) PCA for Glucocerebrosidase with hexaconazole; C, D) PCA for Parkin with hexaconazole.
Table 2.
Stability analysis of the of glucocerebrosidase receptors, parkin complex.
| Ligand-hormone complex | RMSD (nm) | RMSF (nm) | RG (nm) | SASA (nm) |
|---|---|---|---|---|
| Glucocerebrosidase + Hexaconazole | 0.1 ± 0.01 | 0.1 ± 0.02 | 2.3 ± 0.02 | 30 ± 0.01 |
| Parkin+ Hexaconazole | 0.3 ± 0.02 | 0.1 ± 0.02 | 2.5 ± 0.03 | 50 ± 0.02 |
Density-functional theory
The interactions of charge-transfer with the protein binding site are explained by frontier molecular orbitals. Since the orbitals are at their maximum energy, it is simple to remove an electron from the electron-rich HOMO, whereas adding electrons to the lowest-lying orbital in the electron- deficient LUMO looks to be the most energy-efficient. The HOMO and LUMO symbols, respectively, stand for the molecules’ electron-acceptor and-donor properties. The difference between the energy levels of HOMO and LUMO, which denotes an electron’s excitation from the ground state HOMO to the first excited state LUMO, is known as the HOMO-LUMO energy difference. The HOMO-LUMO energy gap is a numerical depiction of the reactivity and stability of the molecules. The estimated HOMO and LUMO energies, as well as the energy gap (E) values, are displayed in Fig. 5. The positive and negative phases of the molecular orbitals are represented by the colors brown and bright yellow, respectively. The ΔE values for LUMO and HOMO of hexaconazole were −1.036 eV and −6.979 eV, respectively.
Fig. 5.
A) LUMO position of Hexaconazole B) HOMO position of Hexaconazole; Positive green, negative orange colour.
Interaction energy of glucocerebrosidase and parkin receptors with hexaconazole
The findings demonstrate that the interaction energy values of hexaconazole with glucocerebrosidase receptors and the parkin receptor were within acceptable limits. The results of the interaction energy support molecular docking results. Details are given in Table 3.
Table 3.
Interaction energy of hexaconazole with glucocerebrosidase and parkin receptors.
| Ligand-protein complex | Coulombic interaction energy (Coul-SR:Protien-Ligand, kJ/mol) | The short-range Lennard-Jones energy (LJ-SR:Protien-Ligand, kJ/mol) |
|---|---|---|
| Glucocerebrosidase+ Hexaconazole | −29.09 ± 14.66 | −122.53 ± 9.8 |
| Parkin+ Hexaconazole | −59.17 ± 14.09 | −104.05 ± 2.4 |
Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA)
MM-PBSA provides information on the quantitative assessment of substrate molecule’s interaction mechanisms. Details for Binding free energy (DG), van der Waals energy and electrostatic energy for hexaconazole with glucocerebrosidase and parkin receptors are given in Table 4.
Table 4.
MM-PBSA of different glucocerebrosidase and parkin receptors with hexaconazole.
| Ligand-hormone complex | Binding free energy (DG) (kJ/mol) | Van der Waals energy (kJ/mol) | Electrostatic energy (kJ/mol) |
|---|---|---|---|
| Glucocerebrosidase+ Hexaconazole | −19.52 ± 1.71 | −35.92 ± 0.74 | −8.41 ± 1.04 |
| Parkin+ Hexaconazole | −19.46 ± 1.37 | −27.70 ± 1.23 | −14.81 ± 0.05 |
Table 5.
ADME properties of hexaconazole.
| Parameters | Hexaconazole |
|---|---|
| GI absorption BBB permeant Log Kp (skin permeation) Molecular weight Topological surface area |
High Yes −5.45 cm/s 314.21 g/mol 50.94 A2 |
The comparative ADME analyses
The comparative ADME properties of hexaconazole were assessed using the Swiss ADME server. Details of ADME are given in Table 4.
Discussion
There are more than 1,600 pesticides for sale that we are exposed to in our daily lives. The sterol demethylation inhibitor hexaconazole is a member of the triazole fungicide family. Because of its wide range of protective and therapeutic actions, hexaconazole is frequently used to prevent fungal diseases brought on by basidiomycetes and ascomycetes on fruit, vegetables, grain crops, etc.26 Environmental and agricultural goods have been found to contain hexaconazole residues which could be harmful to organisms that are not the intended target. Meanwhile, it could enter and accumulate in human bodies through daily diets, providing health concerns to people.26–35 It is important to provide toxicological characteristics of xenobiotics, environmental pollutants, so that precautionary guidelines can be formed for their use. We have done Insilco analysis to predict the toxicological characteristics of hexaconazole and its potency to interact with glucocerebrosidase receptors, including parkin, which has a significant role in the manifestation of Parkinson.
Interference with glucocerebrosidase receptors, A detailed analysis of the biochemistry of the brains of PD-GBA1 patients identified a significant reduction in glucocerebrosidase levels in Substantia nigra (58%), putamen (48%), amygdala (40%), and cerebellum (47%).32 In addition, there is now evidence to support an age-related decline of glucocerebrosidase activity in the aging brain that may act as a predisposing factor for synuclein accumulation and Parkinson.36 Since glucocerebrosidase association has been reported in pathologies in Parkinson, normal homeostasis of glucocerebrosidase is important for a good neurological environment. In our study, hexaconazole showed significant binding energy and molecular interaction with glucocerebrosidase. Our study endorses the case report of David et al.37 that hexaconazole has the potential to disrupt neurological manifestations.37 In addition, at an atomistic level, we performed deep molecular analysis to understand the behavior of hexaconazole on parkin protein because environmental exposure alters or mutates gene regulation, and it has been reported that mutation in the parkin gene is the reason for juvenile Parkinson disease. Furthermore, it has also been reported that environmental exposure or parkin polymorphisms alone seems to influence the age of onset of Parkinson. Our analyses revealed that hexaconazole has −5.67 kcal/mol binding energy with parkin protein, which reflects its interactive potential. These findings reflect the broad toxicological spectrum of hexaconazole. Earlier, it was found that hexaconazole has the potential to disrupt thyroid endocrine disruption in zebrafish. However, recently, it has been found that sub-chronic exposure to hexaconazole may lead to obesity, cardiovascular diseases (CVDs), and hyperlipidemia.38
For the assessment of interactive stability, we have performed MD simulations, and the results show that hexaconazole interacts with glucocerebrosidase and parkin in a stable manner. These findings reveal that hexaconazole may acquire an active site of glucocerebrosidase and parkin and may disrupt the normal function of glucocerebrosidase and parkin at the atomistic level, leading to neurological manifestation. Furthermore, during MD simulation, SASA and PCA represented total expansion of a protein and the surface area of a protein interacting with its solvent molecules, respectively. The data of the study revealed that glucocerebrosidase and parkin with hexaconazole build significant SASA during MD runs. Additionally, as has been shown in Table 4, the binding free energy was computed from the MD trajectories, validating the outcomes of molecular docking and MD simulation. Furthermore, PCA quantifies overall motility of a system by measuring the large-scale average motion of a protein and revealing the structures that underlie atomic fluctuations and eigenvalues. Eigenvalues measure the total motility of the system. The flexibility of the protein was compared under specific situations. Hexaconazole with glucocerebrosidase and the parkin complex occupied significant space, with a stable cluster denoting that the complex is potently stable.
Conclusions
We investigated the molecular interactions between glucocerebrosidase and parkin receptors with hexaconazole. According to the results, hexaconazole may be able to establish potent molecular interaction with glucocerebrosidase and parkin; these proteins have significant roles in normal homeostasis of brain physiology. Hexaconazole may acquire active site of natural ligand which may be reason of neurological manifestation of Parkinson because of hexaconazole exposure. The findings of the study has high significance and are helpful for better assessment of environmental and ecological risk of hexaconazole in inducing Parkinson which contribute to neurodegeneration and requires future assessment.
Supplementary Material
Contributor Information
Faisal K Alkholifi, Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Abdullah bin Amer Street, Riyadh region, Al-Kharj 16278, Saudi Arabia.
Sayed Aliul Hasan Abdi, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Baha University, Al-Baha 65779, Saudi Arabia.
Marwa Qadri, Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia; Inflammation Pharmacology and Drug Discovery Unit, Health Science Research Center (HSRC), Jazan University, Jazan 45142, Saudi Arabia.
Shabihul Fatma Sayed, Department of Nursing, Farasan University College, Jazan University, 54943, Saudi Arabia.
Amani Khardali, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45142 Saudi Arabia; Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia.
Sumathi Nagarajan, Department of Nursing, Farasan University College, Jazan University, 54943, Saudi Arabia.
Alhamyani Abdulrahman, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Baha University, Al-Baha 65779, Saudi Arabia.
Nayef Aldabaan, Department of Pharmacology, College of Pharmacy, Najran University, Najran 61441, Saudi Arabia.
Yahia Alghazwani, Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
Author contributions
All authors contributed equally.
Funding
The authors extend their appreciation to Prince Sattam bin Abdul-Aziz University, Al-Kharj, Saudi Arabia under research grant No. (PSAU/2023/01/9061).
Conflict of interest statement
None declared.
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