{"id":61116,"date":"2024-09-30T11:36:32","date_gmt":"2024-09-30T11:36:32","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=61116"},"modified":"2024-10-09T17:59:25","modified_gmt":"2024-10-09T17:59:25","slug":"molecular-docking-studies-and-antibacterial-evaluation-of-urtica-massaica-leaves","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no3\/molecular-docking-studies-and-antibacterial-evaluation-of-urtica-massaica-leaves\/","title":{"rendered":"Molecular Docking Studies and Antibacterial Evaluation of Urtica massaica Leaves"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Infections\nas a result of microbes are still a major threat to many lives all over the\nworld. To date, the rate of antibiotic resistance is very high with many\nmicro-organisms developing resistance to the available antibiotics1<\/sup>.  At this rate, the urge to have new antibiotic\nformulations as well as investigation of alternative antimicrobial agents\nderived from plants is on course. Herbal medicines are either the mainstay of\nhealthcare delivery or serve as a complement to it across the globe2<\/sup>.<\/p>\n\n\n\n

Herbs\nhave been replacing synthetic compounds for the last few decades. As per the\ndocumentation of the World Health Organization, more than 80 % of the\npopulation in developing countries utilize herbal medicines3<\/sup>. This may be due to their easy availability,\nreduced or no toxic effect, and being able to cover a wide range of conditions4<\/sup>.\nThe literature confirms the anti-oxidant and antibacterial properties of\nthe phytoconstituents including flavonoids, tannins, catechins, vitamins, etc5<\/sup>.\nA mixture of these compounds in herbs can produce better protection than a\nsingle synthetic compound due to synergism. Urtica massaica<\/em> is a\nperennial herb that grows to a height of 200 cm. It’s taxonomically placed in\nthe kingdom Plantae family Urticaceae and genus Urtica. It’s well distributed\nin African countries including Kenya and Uganda where it grows in the forest\nnear the mountains and the cattle areas in homesteads6<\/sup>. In Kenya,\nthis plant has multiple uses including treating rashes and reducing sugar\nlevels. The present study aimed at the antibacterial activities of acetone\nextract of Urtica Massaica<\/em> leaves and docking studies.<\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Plant extract preparation <\/strong><\/p>\n\n\n\n

The plant was collected from rural parts of Kenya and authenticated by the East African Herbarium with a reference number of NMK\/BOT\/CTX\/2\/ID\/2023. The extract was prepared by cold maceration. Briefly, leaf powder 200 g was soaked in 400 ml volume of methanol for 3 days. The flask containing the material was shaken daily, filtered after 72 hours, and concentrated by a rotary evaporator. The resultant extract was packed in clean and pre-weighed glass sample vials and stored for future analysis.<\/p>\n\n\n\n

Antibacterial Activity <\/strong><\/p>\n\n\n\n

The\ndisk diffusion method was used to test the antibacterial potential of Urtica\nmassaica<\/em> extract. The plant extract was used at 250, 200, and 150g\/ml\nconcentrations. Acinetobacter baumannii<\/em> and methicillin-resistant\nStaphylococcus aureus (MRSA) were the targets of the activity. The bacteria\nwere uniformly inoculated onto the Muller Hilton agar media and sterile paper\ndisks laid by sterile forceps using sterile cotton wool swabs. Using a\nmicropipette, exactly 15\u00b5l of the plant extract at various concentrations was\nloaded onto the disks. After being allowed one hour to dry, each plate was\nincubated for 18 hours. A ruler was used to measure the inhibition zones\nsurrounding the disks, and the measurements were recorded in millimeters7<\/sup>.<\/p>\n\n\n\n

Molecular Docking Studies<\/strong><\/p>\n\n\n\n

In\nthis study, molecular docking was performed for flavonoid compounds with\npenicillin-binding protein 2a (PBP 2a)  PDB ID: 4DKI8,9<\/sup> and DNA gyrase\nsubunit B PDB ID: 7PQI10<\/sup>. These proteins were retrieved from the\nRCSB Protein Data Bank (https:\/\/www.rcsb.org). Molecular docking studies were\nperformed using Auto Dock Tools (Version 1.5.7). To investigate docking capacity,\nPBP 2a co-crystallized with Ceftobiprole and DNA gyrase B co-crystallized with\nNovobiocin were selected. Binding cavities of the reference ligand\n(Ceftobiprole and Novobiocin) bind in the crystal structure of proteins were\nselected as docking regions. The docking process was validated by redocking\nwith the co-crystallized ligand. <\/p>\n\n\n\n

In pre-docking, proteins were prepared by removing all water molecules and ligands and adding hydrogen atoms as well as gasteiger charges. On the other hand, all the flavonoid ligands were downloaded from PubChem (https:\/\/pubchem.ncbi.nlm.nih.gov) in the SMILES format and then converted into pdbqt format using online OpenBabel software (https:\/\/www.cheminfo.org). The calculation of free binding energies and prediction of interacting amino acids as well as the number of hydrogen bonds involved with ligands were performed by using a genetic algorithm as a search parameter with 10 runs.<\/p>\n\n\n\n

Data Analysis<\/strong><\/p>\n\n\n\n

Data analysis was conducted using GraphPad prism statistical data analysis software. Descriptive statistics followed to obtain the means and their respective standard error of the means. A significant difference between the concentrations of the extract and that of Ciproflaxacin was obtained through one-way ANOVA followed by fishers pairwise as the post hoc test.<\/p>\n\n\n\n

Results and Discussion<\/strong><\/p>\n\n\n\n

Antibacterial Activity of Urtica massaica<\/em><\/strong><\/p>\n\n\n\n

The antibacterial activity of Urtica massaica<\/em> against resistant strains of A. baumanni<\/em> and MRSA was investigated in this study. The mean zones of inhibition ranged between 9.67\u00b10.33 mm to 6\u00b10.00 mm against MRSA and between 11.67\u00b10.33 mm to 8.33\u00b10.33 mm against A. baumanni<\/em>. The standard antibiotic; ciprofloxacin recorded a mean zone of inhibition of 26\u00b10.00 mm and 30.67\u00b10.67 mm against MRSA and A. baumanni<\/em> respectively. The comparison revealed a significant difference in the mean zones of inhibitions at all the studied concentration levels in against both MRSA and A. baumanni<\/em> (p<0.05). In this analysis for both MRSA and A. baumanni<\/em>, the standard antibiotic; ciprofloxacin recorded a significantly larger mean zone of inhibition while the extract at the lowest concentration of 150 mg\/ml recorded a significantly smaller mean zone of inhibition (p<0.05). <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Graph 1: Comparison of the growth inhibition per concentration level<\/strong><\/p>\n

<\/p>\n

Click here to view Graph<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Molecular Docking Studies<\/strong><\/p>\n\n\n\n

Reported\nflavonoids from Urtica species11, 12 <\/sup>were selected for molecular\ndocking studies. Molecular docking studies were conducted to investigate the\ninhibition potential of phytochemicals specifically flavonoids present in the\nextracts against penicillin binding protein 2a isolated from methicillin resistance\nStaphylococcus aureus and DNA gyrase B isolated from Acinetobacter baumannii.\nThe lowest binding energies score, inhibition constant, number of hydrogen\nbonding and amino acid involved in hydrogen bonding with ligands were captured\nand listed in Table 1 & 2 and its corresponding docking conformation shown\nin Figure 1 & 2. <\/p>\n\n\n\n

Table 1: Docking studies with A. baumanni<\/em> DNA gyrase B ATPase<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

S. No<\/strong><\/p>\n<\/td>\n

\n

Ligand<\/strong><\/p>\n<\/td>\n

\n

Binding Energy<\/strong><\/p>\n

Kcal\/Mol<\/strong><\/p>\n<\/td>\n

\n

Inhibition Constant<\/strong><\/p>\n

T 298.15 K Ki <\/strong><\/p>\n<\/td>\n

\n

No of H- Bonding<\/strong><\/p>\n<\/td>\n

\n

Amino Acids involved <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

Ciprofloxacin<\/p>\n<\/td>\n

\n

-11.05<\/p>\n<\/td>\n

\n

7.89nM<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

GLY91<\/p>\n

THR179<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

Gossypetin<\/p>\n<\/td>\n

\n

-11.99<\/p>\n<\/td>\n

\n

1.62nM<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

GLY91<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

Isovitexin<\/p>\n<\/td>\n

\n

-13.90<\/p>\n<\/td>\n

\n

65.21pM<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

UNL1<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Kaempferol<\/p>\n<\/td>\n

\n

-11.25<\/p>\n<\/td>\n

\n

5.70nM<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n

\n

GLY91<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Myricetin<\/p>\n<\/td>\n

\n

-12.55<\/p>\n<\/td>\n

\n

633.15pM<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

GLY91<\/p>\n

THR179<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

Quercetin<\/p>\n<\/td>\n

\n

-12.00<\/p>\n<\/td>\n

\n

1.60nM<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

GLY91<\/p>\n

THR179<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Docking interactions with A. baumanni<\/em> DNA gyrase B 23kDa ATPase<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Molecular\ndocking studies against DNA gyrase B isolated from A. baumanni<\/em> were found to have binding energies of -13.90 Kcal\/mol\nto 11.05 Kcal\/mol. Ciprofloxacin exhibited binding at the active sites of GLY91\nand THR179 with a binding energy of -11.05 Kcal\/Mol. Among the tested phyto\nconstituents, Isovitexin was found to have a more binding energy of\n-13.90Kcal\/Mol at the active site of UNL1 on A. baumanni<\/em> DNA gyrase B ATPase.<\/p>\n\n\n\n

Table 2: Docking studies with MRSA PBP2a<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

S. No<\/strong><\/p>\n<\/td>\n

\n

Ligand<\/strong><\/p>\n<\/td>\n

\n

Binding Energy<\/strong><\/p>\n

Kcal\/Mol<\/strong><\/p>\n<\/td>\n

\n

Inhibition Constant<\/strong><\/p>\n

T 298.15 K<\/strong><\/p>\n

Ki (nM)<\/strong><\/p>\n<\/td>\n

\n

No of Hydrogen Bonding<\/strong><\/p>\n<\/td>\n

\n

Amino Acids involved in HB<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

Ciprofloxacin<\/p>\n<\/td>\n

\n

-9.95<\/p>\n<\/td>\n

\n

50.97<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

SER403<\/p>\n

ASN464<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

Gossypetin<\/p>\n<\/td>\n

\n

-11.23<\/p>\n<\/td>\n

\n

5.88<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

ASN464<\/p>\n

THR600<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

Isovitexin<\/p>\n<\/td>\n

\n

-12.63<\/p>\n<\/td>\n

\n

552.07pM<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

SER598<\/p>\n

THR444<\/p>\n

TYR446<\/p>\n

HIS583<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Kaempferol<\/p>\n<\/td>\n

\n

-9.83<\/p>\n<\/td>\n

\n

62.66<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n

\n

ASN464<\/p>\n

THR600<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Myricetin<\/p>\n<\/td>\n

\n

-11.04<\/p>\n<\/td>\n

\n

8.14<\/p>\n<\/td>\n

\n

3<\/p>\n<\/td>\n

\n

SER403<\/p>\n

SER462<\/p>\n

TYR446<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

Quercetin<\/p>\n<\/td>\n

\n

-10.58<\/p>\n<\/td>\n

\n

17.57<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

ASN464<\/p>\n

TYR446<\/p>\n

HIS583<\/p>\n

GLU447<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Docking interactions with MRSA PBP2a<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Molecular\ndocking studies against PBP 2a isolated from MRSA were found to have binding\nenergies from -9.83 Kcal\/mol to 12.63 Kcal\/mol. Ciprofloxacin exhibited binding\nat the active sites of SER403 and ASN464 with a binding energy of -9.95\nKcal\/Mol. Among the tested phytoconstituents, Isovitexin was found to have more\nbinding energy of -12.63Kcal\/mol at the active sites of SER598, THR444, TYR446,\nand HIS583 on MRSA PBP2a.<\/p>\n\n\n\n

Amino\nacids involved in the interactions with phytoconstituents match with the amino\nacids involved in binding with co-crystalized ligand (Ceftobiprole and\nNovobiocin) which is retrieved from PDBsum (https:\/\/ebi.ac.uk) and shown in\nFigure 3. The ligand Novobiocin has formed 5 hydrogen bonds with Asn 60, Asp\n87, Asp 95, His 97, and Arg 150 of DNA gyrase B amino acids of DNA gyrase B. In\nour molecular docking study, phytoconstituents formed hydrogen bonding with\nUnl1, Gly91, and Thr179 which are different from amino acids involved with\ncocrystalized ligand Novobiocin. It was found that ligand Ceftobiprole has\nformed 5 hydrogen bonds with Ser 403, Asn 464, Ser 598, Thr 600, and Glu 602\namino acids of penicillin binding protein 2a. In our molecular docking study,\nall the phytoconstituents form hydrogen bonding with penicillin binding protein\n2a at Ser 403, Asn 464, Ser 598, and Thr 600 like co-crystalized ligand\nCeftobiprole.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 3: Ligand and enzyme interactions for 7PQI and 4DKI with Novobiocin and Ceftobiprole<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The spreading of resistant pathogenic bacteria is now\nan alarming threat to public health both in developed countries and developing\ncountries. Recent literature according to the China Antimicrobial Resistance\nSurveillance System from a period of 2019- 2020 confirms the occurrence of\nvarious gram-positive and gram-negative resistant micro-organisms. In case of\nno effective measures, the deaths due to antibiotic resistance will reach 10\nmillion by 2025 13<\/sup>. This situation demands the development of\ncompounds against resistant organisms. Research is focusing on plants to tackle\nantibiotic resistance. Plants contain various phytochemical constituents, such\nas alkaloids, flavonoids, tannins, saponins, phenols and terpenoids are proven\nfor therapeutic activities including antibacterial capability. Worldwide, the\nusage of herbal medicine is increasing and is projected to increase by 5.5% by\n202714<\/sup>. Dependency on herbal medicine in African countries is more\nthan 60% for health benefits. Africa is rich in many plant species with diverse\nhealth benefits including combating drug resistance and further research\nfocusing on new identifications against bacterial resistance is critical for\ncombating bacterial resistance in Africa and globally 15<\/sup>. <\/p>\n\n\n\n

Current research aimed at screening Urtica massaica<\/em>\nagainst resistant bacteria. Urticaspecies are found mostly in Europe,\nNorth America, and North Africa along with some parts of Asia. In 2018, 46\nspecies of Urtica were reported along with their habitat, phytochemical\nconstituents, and antibacterial activity. Urtica Dioica<\/em> dominated the\nreports mentioned about antibacterial studies. Information about Urtica\nmassaica <\/em>and studies from Africa are not reported in the review16<\/sup>.\nIn 2019, the antibacterial activity of Urtica massaica <\/em>leaf extract was\npublished against Staphylococcus aureus and Escherichia coli. The zone of\ninhibition reported was between 6mm- 8.4mm at 100mg\/mL17<\/sup>. Other\nstudies from Africa (Rwanda) included about Phytochemical screening and\nantibacterial activity of stem and root bark extracts against Escherichia coli,\nSalmonella sp., and Staphylococcus aureus. The maximum zone of inhibition is\n28mm at 600mg\/mL18<\/sup>. <\/p>\n\n\n\n

Molecular docking studies in recent research are used\nas a powerful tool to predict the activity of compounds against the target\nreceptor. A very recent study confirmed the presence of phenolic and flavonoid\ncontents along with anti-inflammatory and molecular docking studies against\ncyclooxygenase-211<\/sup>. Among the tested active constituents, Kaempferol\nwas found to have the least binding energy indicating more chances of binding\ninto the target site for both the selected proteins. Kaempferol-containing plants are gaining importance in clinical\nmicrobiology and literature supports the activity of extracts containing\nKaempferol and its derivatives against resistant microorganisms like A. baumanni <\/em>and MRSA19<\/sup>. Docking and antimicrobial studies confirm the\npotential of Urtica massaica <\/em>against the selected resistant\nmicroorganisms.  <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

The results from the in vitro antibacterial activity\nof Urtica massaica<\/em> in the present\nstudy showed that Urtica massaica<\/em> is\na potential antimicrobial agent. The ability of extract could be attributed to\nvarious phytochemical compounds present in plants such as the phenolic and\nflavonoid compounds in the extract. It\u2019s therefore evident that this plant\ncould be of help in inhibiting the progression of the oxidative stress that\naids in the pathogenesis of chronic life-threatening disorders. Molecular\ndocking studies also confirmed the same giving a way forward to investigate\nfurther on Urtica massaica <\/em>to isolate the individual compounds and prove\nthem for the antimicrobial activity against resistant microorganisms.<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

The authors express their deep sense of gratitude to\nthe management and research team of Mount Kenya University for their\nencouragement in the successful completion of this work. <\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors\ndo not have any conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The author(s) received no financial\nsupport for the research, authorship, and\/or publication of this article.<\/p>\n\n\n\n

Data Availability Statement<\/strong><\/p>\n\n\n\n

This statement does not apply to this article.<\/p>\n\n\n\n

Ethics Statement<\/strong><\/p>\n\n\n\n

This research did not involve human participants, animal subjects, or any material that requires ethical approval.<\/p>\n\n\n\n

Informed Consent Statement<\/strong><\/p>\n\n\n\n

This study did not involve human participants, and therefore, informed consent was not required<\/p>\n\n\n\n

Authors\u2019 Contribution<\/strong><\/p>\n\n\n\n

Bindu Madhavi Boddupalli: Conceptualization; Manuscript writing; Statistical design<\/p>\n\n\n\n

Ramalingam Ramani: Molecular docking studies and analysis<\/p>\n\n\n\n

Elizabeth Owiti: Execution of the work<\/p>\n\n\n\n

Elias Nelson: Procurement of materials and part of execution<\/p>\n\n\n\n

Michael Mungoma: Manuscript proof reading and analysis<\/p>\n\n\n\n

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