ANTI-STAPHYLOCOCCUS AUREUS ACTIVITY, ADMET PROPERTIES AND MOLECULAR DOCKING STUDY OF PHYTOCOMPOUNDS FROM ERIANTHEMUM DREGEI

ANTI-STAPHYLOCOCCUS AUREUS ACTIVITY, ADMET PROPERTIES AND MOLECULAR DOCKING STUDY OF PHYTOCOMPOUNDS FROM ERIANTHEMUM DREGEI

Tsolanku Sidney Maliehe ^*, Nokuthula Nomusa Mthembu and Shandu Jabulani Siyabonga

Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.

ABSTRACT: The constant increase in the emergence of multidrug resistance among Staphylococcus aureus strains threatens public health. The study aimed at evaluating the anti-S. aureus activity, pharmacokinetic properties, and interactions of compounds from Erianthemum dregei with proteins in S. aureus. Anti-S. aureus activity was investigated by broth dilution method while gas chromatography-mass spectrometry (GC-MS) was used to identify the compounds. The drug-likeness, pharmacokinetic and toxicity profiles of the compounds were predicted by SwissADME and PreADMET tools. AutoDock Vina was used to assessing the binding affinities of the docked ligand-receptor complexes. The extract revealed the minimum inhibitory concentration value of 0.78 mg/mL. Phytol (93.58%) and 3-tetradecyn-1-ol (6.42%) were the main constituents. In-silico predictions suggested both compounds to have drug-like properties as they adhered to the Lipinski’s rule of five. Phytol was found to have non-mutagenic effects, while 3-tetradecyn-1-ol was predicted to be mutagenic. The compounds were non-carcinogenic on mice models and carcinogenic on rat`s. Phytol has a binding affinity to DNA-gyrase and FtsZ with docking energy values of -4.1 and -5.3 kcal/mol, respectively, whereas the docking scores for 3-tetradecyn-1-ol against DNA-gyrase and FtsZ were -3.9 and -5.0 kcal/mol. The results revealed the extract to have a noteworthy activity against S. aureus, with its identified compounds having desirable pharmacokinetics.

Phytol, 3-Tetradecyn-1-ol, Staphylococcus aureus, Pharmacokinetics, Molecular docking

INTRODUCTION: Staphylococcus aureus is a member of the family Micrococcaceae that are characterized as catalase-positive and Gram-positive aerobic coccus ¹. It is known to cause clinical manifestations such pneumonia, endo-carditis, toxic shock syndrome, cellulitis, abscesses and impetigo at varying severity in humans ². Its infections are most predominant in developing countries, especially among the elderly, young children, and immunosuppressed people ³.

Different strains of S. aureus harbour a combination of different virulence genes, which express factors used for adherence, colonisation, invasion and infectiousness ¹.

S. aureus infections are exacerbated by the constant increase in the emergence of multidrug resistance, which threatens global public health ⁴. Generally, S. aureus resists the effects of anti-microbial agents through enzymatic inactivation of the anti-microbials, modification of target protein receptors, and extrusion by efflux pulp ⁵.

Major contributors to its resistance are; (1) the inappropriate use of anti-microbials, (2) intake of improper dosages, and (3) excessive use of anti-microbials ⁶. Methicillin-resistant S. aureus strains have become increasingly prevalent among both nosocomial and community-acquired infections ⁷. Some strains have also shown resistance to vancomycin, one of the anti-microbials of the last resort ⁸. It is, therefore, imperative to search for new compounds which are characterized by high potency.

Medicinal plants are the predominant sources of bioactive compounds used in modern-day drug discoveries and developments ⁹. Over 50% of drugs on the market shelves currently have their origin in medicinal plants ¹⁰. This is because of the high accessibility, efficacy, and generally low side effects of plant-based products ¹¹. A high percentage of medicinal plants are reported to have anti-microbial effects. The excellent potency and pharmacotherapeutic effects are owed to their diverse bioactive compounds such as phenolics, saponins, tannin, alkaloids, and steroids ¹². Nevertheless, the majority of the newly discovered compounds are rejected in the last stages of drug discovery processes due to poor pharmacokinetic profiles ^{13, 14}.

The pharmacokinetic profiles of compounds describe their absorption, distribution, metabolism, and excretion (ADME) properties ¹⁵. The consi-deration of evaluating the ADME characteristics at the early stages of drug discovery can reduce the pharmacokinetics-related failures. Although the classic methods used to assess pharmacokinetics are feasible, they take a considerable length of time and are expensive ¹⁶. Recently, computational ADME methods are becoming the methods of choice in the assessment of ADME and toxicity properties at the early stages of drug discovery.

In the last decade, many ADME prediction models have been reported and have yielded outstanding results as several drugs have been identified using these approaches ¹⁷. The in-silico methods turn to offer valuable direction prior to the commencing of in-vitro and in-vivo experiments ¹⁸. They provide advantages for practical findings and assessment of mechanisms of actions. Since there are many pharmacological targets and because most compounds demonstrate pleiotropic effects by interacting with different targets, computational models help in finding the precise targets. Thus, the most prospective compounds among an array of compounds can be easily and quickly identified and validated. In addition, they help in making cost-effective assessments prior to the costly process of drug development ¹⁹. Although, in-silico methods are well established in medicinal synthetic chemistry, their application in the field of natural compounds is still underexplored ²⁰.

Erianthemum dregei is a parasitic shrub belonging to Loranthaceae family. It is widely distributed in the northern part of KwaZulu-Natal, South Africa ²¹. E. dregei has been used in treatments of sexually transmitted diseases, snake bites, and stomach ailments ²². However, there are limited scientific studies confirming the medicinal properties of this plant.

The purpose of this study was to evaluate the antibacterial activity of E. dregei `s methanolic leaf extract against S. aureus and assess the chemical composition of the extract using gas chromato-graphy-mass spectrophotometer (GC-MS). Moreover, the drug-likeness of the identified compounds was assessed based on their physicochemical properties using SwissADME and PreADME online tools. The pharmacokinetic parameters, bioactive scores, and ligand-protein interactions were also predicted by SwissADME, Molinspiration, and Autodock-Vina tools, respectively.

MATERIALS AND METHODS:

Plant Collection and Extraction: The leaves of E. dregei were sampled from Manguzi and transported to the University of Zululand, South Africa (28 °45 ′S31 °54 ′E). The plant was authenticated by Dr. Ntuli, Department of Botany, University of Zululand, at the University Herbarium. The plant was allocated specimen number NNM01. The leaves were washed with tap water, dried at room temperature, and milled to a fine powder. Plant material (20 g) was extracted with 200 mL of methanol (technical grade, Merck) at room temperature at a shaking speed of 130 rpm for 48 hours. Thereafter, it was filtered using Whatman No.1 filter paper before being transferred into a pre-weighed glass container. The methanol was removed by evaporation under a stream of air in a fume-hood.

Minimum Inhibitory Concentration (MIC): The extract was evaluated for its antibacterial activity against Staphylococcus aureus (ATCC 25923). Prior to the antibacterial activity test, the bacterium was resuscitated on nutrient broth and incubated at 37 °C. After overnight incubation, McFarland standard was used to standardize the inoculum density of the bacterium (1 × 10⁶ CFU/mL) using a spectrophotometer (Spectroquant-Pharo 100). The MIC of the extract was assessed using the broth dilution method in a sterile 96-well plate. Mueller-Hinton broth (50 μL) was added into the wells, and 50 μL of 100 mg/mL of the extract was added to the first row. Serial dilution was performed to vary the concentrations (50 - 0.3 mg/mL). About 50 μL of the bacterial suspension was separately pipetted into the wells, and the plate was incubated at 37 °C. After overnight incubation, 40 μL of p-iodo-nitrotetrazolium violet (0.2 mg/mL) was added into each well and incubated at 37°C for 15 minutes. The lowest concentration that inhibited the growth of S. aureus (ATCC 25923) was considered as the MIC ²³.

Minimum Bactericidal Concentration (MBC): Bactericidal effect of the extract was investigated on nutrient agar. Briefly, each well that demonstrated no visible bacterial growth during MIC evaluation was streaked on nutrient agar plates. Thereafter, the agar plates were incubated at 37 °C for 24 h. The lowest concentration to induce a bactericidal effect on S. aureus (ATCC 25923) was considered as MBC ¹².

Phytochemical Analysis: A phytochemistry test of the methanolic extract was done using GC-MS. The GC oven temperature was initially adjusted to 40 °C for 3 minutes and subsequently raised by 5 °C per minute to 220 °C. The injector temperature was set at 250 °C, and the flow rate of helium gas was 1.0 mL per minute, with a 10:1 split ratio. The MS system had an ion source temperature of 250 °C and voltage of 70 eV ²⁴.

Physicochemical and Pharmacokinetic Properties: SwissADME online tool was utilized to determine the physicochemical and pharmacokinetic properties of the identified phytocompounds. The simplified molecular-input line-entry system (SMILES) for each compound was produced by the structure file generator, available at the SwissADME tool, after drawing their 2-dimensional structures. Thereafter, the physicochemical descriptors such as the molecular weight (MW), number of hydrogen bond acceptors (nHBA), number of hydrogen bond donors (nHBD), and number of rotatable bonds (nRB) were computed. The lipophilicity was evaluated using a consensus logP (cLog P) estimation ^{25, 26}. The aqueous solubility (LogS) was assessed using the three predictive models, namely ESOL, Ali, and SILICOS-IT. The pharmacokinetic properties such as human intestinal absorption (HIA), penetration of the blood-brain barrier (BBB), the interaction of compounds with P-glyco-protein (P-gp), metabolism, and skin permeability (LogKp) were predicted ²⁶.

Drug-likeness Prediction: The drug-likeness assessment was carried out using the validated rules used as filters in many pharmaceutical companies, as follows: Lipinski, Ghose, Veber, and Egan. Moreover, the bioavailability scores of the compounds were computed based on their molecular weight, cLogP, number of hydrogen bond acceptors, and hydrogen bond donor ^{26, 27}.

Bioactivity Scores: Bioactivity scores of the compounds were predicted using software Molin-spiration score online. The scores were evaluated against G protein-coupled receptors (GPCR ligand), ion channel modulator, a kinase inhibitor, nuclear receptor ligand, protease inhibitor, and enzyme inhibitor ²⁸.

Toxicological Study: The toxicological properties of the compounds were computed using the online server PreADMET. The 2D structural models of the compounds were drawn, and each compound was screened to determine its mutagenicity and carcinogenicity properties and the risk of inhibiting the human ether-a-go-go-related (hERG) gene ²⁹.

Molecular Docking Study:

Retrieval and Preparation of the Receptors: The three-dimensional structures of the two target receptor proteins were retrieved from the Protein Data Bank (PDB). The receptor proteins were DNA-gyrase (PDB: ID5z9n) and FtsZ(PDB ID: 3v08). DNA-gyrase is responsible for DNA replication, while the FtsZ enzyme plays an important role in cell division ³⁰. The structures were loaded into the Biovia Discovery Studio 4.1 Visualizer. The water molecules, heteroatoms, and ligands were deleted. Thereafter, polar hydrogen was added to the proteins.

Ligand Preparation: The structures of the identified compounds and ciprofloxacin (control) were procured from the National Centre for Biotechnology Information (NCBI) PubChem compound database. The compounds were downloaded in Structure-Data File (SDF) format and converted to PDB coordinates using Biovia Discovery Studio 4.1 visualizer and energy minimised.

Docking and Visualisation of the Complexes: The docking of the target proteins with the ligands was done using AutoDock Vina ³¹. Docking was performed to get a set of possible conformations and orientations for the ligand at the binding site. The ligand displaying the lowest binding affinity was chosen as the best conformation. The docked protein-ligand complexes were visualized using Biovia Discovery Studio 4.1 Visualiser to analyze the formed interactions.

RESULTS AND DISCUSSION:

Antibacterial Activity: The extract was tested for its in-vitro antibacterial activity against S. aureus ATCC 25922. S. aureus (ATCC 25923) was susceptible against the extract with the MIC value of 0.78 mg/mL Table 1. The extract was more effective than the positive control-ciprofloxacin, which gave the MIC value of 3.13mg/mL. Gram-positive strains are often susceptible to most anti-microbial agents due to their outer membrane, which tends to allow some anti-microbials to penetrate the bacterial cells by and inhibit the bacterial growth through different mechanisms ³². The extract demonstrated an MBC value greater than 50 mg/mL against S. aureus ATCC 25922 Table 1. This implied that the extract has only bacteriostatic effect at the utilized concentrations. Nevertheless, the results imply that the extract has the potential to be used as a source of therapeutic antibacterial compounds.

TABLE 1: MINIMUM INHIBITORY CONCENTRATION AND MINIMUM BACTERICIDAL CONCENTRATION OF THE EXTRACT

Chemical Composition: The GC-MS chroma-togram profile revealed the presence of 3, 7, 11, 15-tetramethyl-hexadecen-1-ol also known as phytol (93.58%) and 3-tetradecyn-1-ol (6.42%) Table 2 and Fig. 1. Phytol is a diterpene used as precursor for vitamin K and is recognised for its anti-microbial, anticancer, ant-inflammatory, anti-diuretic, hypocholesterolemic and antioxidant activities ³³. 3-Tetradecyn-1-ol is an alcoholic compound that has antibacterial effect ³⁴. Thus, the compounds were assumed to have contributed to the antibacterial activity of the extract against S. aureus (ATCC 25923).

TABLE 2: PHYTOCOMPOUNDS IDENTIFIED BY GC-MS

FIG. 1: A GC-MS CHROMATOGRAM PEAK PROFILE OF METHANOLIC ENCEPHALARTOS FEROX FRUIT EXTRACT

MW, nHBA and nHBA: The molecular weight (MW) played a pivotal role in the drug action: the higher the MW (MW≤500 g/mol), the poorer the absorption and bioavailability ³⁵. The MW of phytol and 3-tetradecyn-1-ol were calculated and the results are shown in Table 3. Phytol and 3-tetradecyn-1-ol were found to be 296.5 g/mol and 210.36 g/mol, respectively. This implied that both compounds have the potential to be easily absorbed and transported as they comply with the Lipinski’s rule of five concerning MW. The number of hydrogen bond acceptor (nHBA) and hydrogen bond donors (nHBA) were calculated, and the results are illustrated in Table 3. The results indicated that both phytol and 3-tetradecyn-1-ol have one hydrogen bond acceptor and one hydrogen donor. Lipinski’s rule of five states that the drug-like compounds ought to have less than or equal to ten hydrogen bond acceptors (nHBA ≤ 10) and less than or equal to five hydrogen bond donors (nHBA ≤ 5). Based on the obtained results, both compounds have a potential for eventual development as oral agents and are potentially active drug candidates.

TABLE 3: THE PHYSICOCHEMICAL PROPERTIES AND LIPOPHILICITY OF THE IDENTIFIED COMPOUNDS

nRB and cLogP: The number of rotatable bonds(nRB) is a measure of molecular flexibility and is one of the widely used filters during drug discovery process ³⁶. Table 3 displays the nRB of the two identified compounds. 3-Tetradecyn-1-ol has nine rotatable bonds, while phytol possesses 13 rotatable bonds. Therefore, only 3-tetradecyn-1-ol adhere to the filter, which states that the number of rotatable bonds ought to be ≤ 10³⁷. This means that phytol exhibits low conformational flexibility in comparison to 3-tetradecyn-1, hence it has a high probability of being bioavailable. The lipophilicity (cLogP) of the compounds is a quality that is used to calculate their hydrophilicity. The cLogP plays a major role in ADME processes of drug-like compounds, consequently influencing their therapeutic potential and adverse effects ³⁸. The cLogP values of phytol and 3-tetradecyn-1-ol were calculated and the results are displayed in Table 3. Phytol was estimated to have cLogP value of 6.22 whereas 3-tetradecyn-1-ol has cLogP value of 4.27. Low cLogP values (cLog P≤5) translate better absorption and bioavailability and vice versa. On this basis, only 3-tetradecyn-1-ol has a reasonable probability of good bioavailability as it has cLogP value less than 5.

Solubility Properties: The aqueous solubility of a compound is a significant parameter that greatly affects its absorption and distribution characteristics ³⁹. Typically, low solubility goes along with a poor absorption, and therefore the general aim is to avoid poorly soluble compounds. The solubility of the identified compounds is demonstrated in Table 4. The results revealed that phytol is moderately soluble to poorly soluble while 3-tetradecyn-1-ol is soluble to moderately soluble, depending on the LogS prediction model. Thus, it was concluded that both compounds have the potential to be absorbed and available in the biological systems ⁴⁰.

TABLE 4: SOLUBILITY PREDICTIONS OF THE IDENTIFIED COMPOUNDS

Pharmacokinetic Properties: The gastrointestinal absorption (GIA) of the identified compounds was evaluated, and the results are presented in Table 5. Phytol was estimated to have low GIA, while 3-tetradecyn-1-ol demonstrated high potential being absorbed in the gastrointestinal tract. High GIA is considered an advantage during oral administration. Thus, only 3-tetradecyn-1-ol has good probability of being absorbed in the intestinal cells in comparison to phytol. The blood-brain barrier (BBB) is the endothelial cell layer of the brain that separates the brain from the blood. It regulates the exchange of drug-like compounds between blood and brain ⁴¹. The ability of the identified compounds to permeate through BBB was predicted, and the results are illustrated in Table 5. 3-Tetradecyn-1-ol demonstrated the potential to penetrate through the BBB, whereas phytol did not. The ability of compounds to penetrate BBB is of advantage for compounds needed in the central nervous system (CNS) whereas BBB permeability ought to be minimised for non-CNS compounds to avoid adverse side-effects ⁴². Based on the results, 3-tetradecyn-1-ol is a good candidate for treating diseases affecting CNS. The prediction of P-glycoprotein (P-gp) substrates facilitates early identification and elimination of drug candidates of low efficacy. The effects of the compounds on P-gp are illustrated in Table 5. Phytol showed the potential to act as a substrate of P-gp, whereas 3-tetradecyn-1-ol did not. P-gpis an ATP-dependent efflux transporter which is a product of the gene that confers multidrug resistance ⁴³. Thus, the over-expression of P-gp may hamper the therapeutic activities of phytol and not 3-tetradecyn-1-ol.

TABLE 5: THE PHARMACOKINETIC PARAMETERS OF THE PHYTOCOMPOUNDS

Metabolism of compounds influences their absorption, distribution, and excretion. Cytochrome P450 (CYP) monooxygenase is a class of enzymes that influences drug metabolism and elimination in the body ⁴⁴. The computed metabolism of the identified compounds against five isomers of CYP is displayed in Table 5. It was observed that phytol has the potential to only inhibit CYP2C9 while 3-tetradecyn-1-ol is an inhibitor of CYP1A2. Thus, majority of the tested CYP isomers were not inhibited by the two compounds.

This means that the compounds have a high probability of being metabolised and exert their activity at the targeted sites, and eliminated thereafter. The skin perme-ability (LogKp) is an important parameter for the investigation of compounds that require trans-dermal administration ⁴⁵. The skin permeability of the identified compounds was predicted, and the results are shown in Table 5.

Phytol and 3-tetradecyn-1-ol had -2.29 cm/s and -3.75 cm/s, respectively. Thus, both compounds were predicted to be impermeable through the skin as they both have a negative LogKp. This means that alternative routes are to be adapted when ministering to them. Moreover, the compounds do not present any risk upon contact with the skin ⁴⁶.

Drug-likeness and Bioavailability: Lipinski rule of five is the widely used filter for drug-like properties ⁴⁷. According to Lipinski rule of five, compounds are likely to be accepted as orally active when they have: less than 5 hydrogen bond donor (nHBD ≤ 5), less than 10 hydrogen bond acceptors (nHBA ≤ 10), molecular weight ≤ 500 Da and clogP value≤5. Moreover, compounds that violate more than one of the rules are assumed to display difficulties in bioavailability ²⁶. The drug-likeness of the identified compounds is displayed in Table 6. Phytol and 3-tetradecyn-1-ol proved to comply with Lipinski rule. Based on the observed results, both compounds have the potential to be good drug candidates. Moreover, although phytol complied only with Lipinski rule, 3-tetradecyn-1-ol was also found in compliance with other filters such as Ghose, Veber, and Edgan.  The bio-availability of phytol and 3-tetradecyn-1-ol were computed, and the results are shown in Table 6. Both compounds were predicted to have 55% (0.5) probability of achieving the bioavailability endpoints.

Normally, the amount of the compounds which reach the systemic circulation is less than the administered dose. However, compounds that display more than or equal to 50% probability of being bioavailable are generally accepted ⁴⁸. Thus, both compounds are an advantage as they displayed more than 50% probability of being bioavailable upon administration⁴⁹.

TABLE 6: DRUG-LIKENESS AND BIOAVAILABILITY SCORES OF THE COMPOUNDS

Bioactive Scores: The bioactivity scores of the compounds are represented in Table 7. According to the bioactivity score evaluation parameters, compounds are interpreted as active (scores > 0), moderately active (scores: -5.0-0.0) and inactive (bioactivity score < -5.0) ⁵⁰. Phytol was revealed to be active against all tested parameters, except against kinase where it showed moderate activity. 3-Tetradecyn-1-ol is active as an ion channel modulator, nuclear receptor ligand, and enzyme inhibitor. It also demonstrated moderate activity against other tested proteins. Thus, these compounds have the potential to treat diseases caused by hyperactive protein kinases, protease, and other enzymes. Moreover, since nuclear receptors are key regulators of some metabolic disorders such as cancer, both compounds are promising therapeutic alternatives against such diseases ⁵¹. In general, both compounds can be used as pharmacological agents against various diseases.

TABLE 7: BIOACTIVITY SCORES OF THE PHYTO-COMPOUNDS

Toxicological Studies: The mutagenicity, carcinogenicity, and capability of the compounds to inhibit hERG were evaluated using PreADMET, and the results are displayed in Table 8. Ames toxicity test was employed to predict the mutagenicity of the compounds. Phytol was found to have non-mutagenic effects, while 3-tetradecyn-1-ol was predicted to be mutagenic. This means that only 3-tetradecyn-1-ol has the potential to alter the genetic makeup in biological systems, consequently causing undesirable side effects and neurodegenerative diseases ⁵². Carcinogenicity is the capability of the compounds to induce modifications that can lead to cancer in the cells ⁵³. According to PreADMET, the negative prediction translates clear evidence of carcinogenic activity, whereas positive means the compounds are not carcinogenic ²⁹. The carcinogenic profiles of the compounds revealed that both phytol and 3-tetradecyn-1-ol were non-carcinogenic on the mouse and carcinogenic on rats. Moreover, both compounds are unlikely to inhibit hERG gene as they demonstrated low risks. Inhibition of the hERG gene has been strongly associated with prolonging QT syndrome, which often results in sudden heart attacks ⁵⁴.

TABLE 8: TOXICOLOGICAL PROPERTIES OF THE PHYTOCOMPOUNDS

Molecular Docking: Anti-microbial agents (ligands) inhibit cell wall synthesis, nucleic acid synthesis, protein synthesis, and metabolic pathways by binding to the specific proteins which are responsible for biological activities ⁵⁵. To understand the mechanism of anti- S. aureus activity of the identified ligands, a molecular docking study was carried out. The binding energy of the selected proteins against the identified ligands is tabulated in Table 9. The results show that phytol has a binding affinity to DNA-gyrase and FtsZ with docking energy values of -4.1 and -5.3 kcal/mol, respectively. The docking scores for 3-tetradecyn-1-ol against DNA-gyrase and FtsZ are -3.9, and -5.0 kcal/mol. The positive control-ciprofloxacin displayed the binding energy scores of -6.9 1 kcal/mol against DNA-gyrase and -7.1 kcal/mol against FtsZ. Protein-ligand binding occurs extemporaneously when the free energy change is negative. The negative energy scores signpost the stability of the protein-ligand complexes, and the lower the binding free energy, the better the binding affinity. The compounds showed binding scores that correlate to the moderate binding affinity. However, phytol revealed the lowest free binding energy against all selected receptor proteins in comparison to 3-tetradecyn-1-ol, indicative of better binding affinity than 3-tetradecyn-1-ol. Nevertheless, both compounds showed binding energy lower than the standard drug-ciprofloxacin, which displayed the binding energy in the range of -6.91 kcal/mol with DNA-gyrase and -7.1 kcal/mol with FtsZ. The efficacy of weak binders like the identified compounds in comparison to the positive control-ciprofloxacin might be due to the high dissociation rates they possess and the likelihood to bind to a large number of various targets in S. aureus ⁵⁶.

TABLE 9: MOLECULAR DOCKING ANALYSIS OF THE COMPOUNDS WITH DIFFERENT RECEPTOR PROTEINS

Hydrogen and other interactions are contributors to binding affinities and the stabilities of ligand-receptor complexes. The H-bond interactions and the number of other interactions of the selected receptors against the identified ligands are displayed in Table 9, Fig. 2, and Fig. 3.

FIG. 2: 2 DIMENSIONAL (2D) AND 3 DIMENSIONAL (3D) STRUCTURES OF DOCKED COMPLEXES. A AND X ARE 2D AND 3D OF PHYTOL-DNA-GYRASE COMPLEXES. B AND Y ARE 2D AND 3D OF PHYTOL-FTSZ COMPLEXES

FIG. 3: 2D AND 3D STRUCTURES OF DOCKED COMPLEXES. X AND A ARE 2D AND 3D OF 3-TETRADECYN-1-OL -DNA-GYRASE COMPLEXES. Y AND B ARE 2D AND 3D OF 3-TETRADECYN-1-OL -FTSZ COMPLEXES

Although phytol manifests poor binding energy for DNA-gyrase, it showed the highest number of H-bonds. Phytol revealed three H-bonds with the amino acids ILE A:94, VAL A:97, and SER A:121. It also demonstrated alkyl interactions with ILE A:78 and PRO A:A:79 and van der Waals interactions. 3-Tetradecyn-1-ol displayed one H-bond with SER A:121, alkyl interactions with ILE A:94 and ILE A:78 and van der Waals bonds with the remaining residues. With FtsZ protein, phytol revealed H-bonds with the amino acids GLY A:34 and GLN A:195. Other interacting forces that occurred are alkyl (VAL A:307, VAL A:297, VAL A:203, and ILE A:228) and van der Waals interactions. THR A:265 and ASN A:263 of FtsZ formed H-bonds with 3-tetradecyn-1-ol. The ligand also interacted through alkyl bonds with ILE A:228, VAL A:307, VAL A:203 and VAL A:297 and van der Waals forces with the rest of the residues. The results imply that the two compounds have the potential to inhibit S. aureus by forming biological interactions with the target proteins, consequently resulting in the inhibition of the metabolic reactions ⁵⁵.

CONCLUSION: The extract revealed noteworthy antibacterial activity against S. aureus (ATCC 25923). Phytol and 3-tetradecyn-1-ol were the main chemical constituents. Both compounds demonstrated to have drug-like and desirable ADME properties. The drug-like property predictions showed that both compounds comply with the Lipinski rule of five. Phytol was found to be non-mutagen but carcinogenic on rat models. Nevertheless, 3-tetradecyn-1-ol is estimated to cause mutagenic effects and carcinogenic effects in rats.

Both compounds demonstrated a margin of safety as they have low probabilities of acting as hERG inhibitors. The compounds showed abilities to inhibit bacterial growth through interaction with DNA-gyrase and FtsZ proteins. Further research needs to be undertaken using in-vitro and in-vivo methods to validate the predictive results.

ACKNOWLEDGEMENT: The authors would also like to acknowledge the staff and postgraduate students in the Department of Biochemistry and Microbiology for their outstanding support.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

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    How to cite this article:

    Maliehe TS, Mthembu NN and Siyabonga SJ: Anti-staphylococcus aureus activity, admet properties and molecular docking study of phytocompounds from Erianthemum dregei. Int J Pharm Sci & Res 2021; 12(6): 3349-59. doi: 10.13040/IJPSR.0975-8232.12(6).3349-59.

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