Browsing by Author "Faya, Andile Kennedy Mbuso."
Now showing 1 - 3 of 3
- Results Per Page
- Sort Options
Item Erythromycin, Roxithromycin, Azithromycin and Clarithromycin targeting the SARS-COV-2 spike protein: a molecular dynamics study.(2022) Naidoo, Eustacia.; Faya, Andile Kennedy Mbuso.The Covid-19 global pandemic has taken the lives of many people and has left the health sector in ruins. There is a desperate need for the scientific and medical community to pose new strategies to combat this virus. One way is repurposing of already existing drugs for the safe treatment of Covid-19. In view of the above facts, the present research project work was planned and aimed to identify the mechanism of inhibition of macrolides by evaluating them in silico against the SARS-CoV-2 spike protein. We performed molecular dynamics and molecular docking studies on the following macrolide antibiotics: azithromycin, erythromycin, clarithromycin and roxithromycin, and we compared these with the results achieved from our controls (Ivermectin and Remdesivir). Our ligands were prepared using chemdraw and chimera software. Protein data bank was used to retrieve the four receptors: 3CLpro (6LU7), native human ACE2 (1R42), RdRp (6M71) and spike RBD-ACE2 (6LZG)). AutoDock Vina software was used to perform all docking experiments. Fitting analyses were performed using PyMOL and Biovia Discovery Studio. GROMACS was used for molecular dynamics studies to determine RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation) values. We then went on to determine the intermolecular hydrogen bonding present, as well as the distances of the ligand whilst inside the pocket. Our findings revealed that all the macrolide antibiotics portrayed similar results with each other, as well as with each of our controls (Ivermectin and Remdesivir). Each of the macrolide antibiotics showed strong binding with each of the four receptors. However, azithromycin showed the greatest binding potential (-7.9 kcal/mol) relative to the two controls (Ivermectin (-10.4 kcal/mol) and Remdesivir (-8.5 kcal/mol)). Azithromycin-ACE2 complex showed the least deviation to the ACE2 protein and is therefore the most similar. The average RMSF values shows that there are potential interactions of azithromycin with the receptor protein (ACE2). Covid-19 emerged in 2019, and to this date, 2022, there is no known cures. There have been vaccines like Johnson and Johnson and Pfizer which have been tried and tested and has shown to reduce severity of disease and minimize fatality. However, due to the new emerging strains, there is a continuous need for new therapeutic interventions. Azithromycin has also showed similar results to both Ivermectin and Remdesivir (controls), showing great binding affinity for the ACE-2 receptor. Our analysis based on molecular dynamics simulation and MM-PBSA binding free energy calculation suggests that azithromycin, erythromycin, clarithromycin and roxithromycin could serve as SARS-CoV-2 inhibitors, hence an alternative solution to treat COVID-19 upon further clinical validation.Item Nanoencapsulation of novel pyrazolone-based compounds to enhance solubility and biological activity.(2022) Igbokwe, Nkeiruka Nkeonyere.; Faya, Andile Kennedy Mbuso.; Karpoormath, Rajshekhar.The biological activity of pyrazolone-based derivatives has been thoroughly documented; nonetheless, low stability and water solubility are their main drawbacks, preventing effective translation to clinical application. Based on this, two previously reported weakly soluble pyrazolone-based compounds, PBC-301 and PBC-302, were encapsulated using PLGA: poloxamer complex to improve their solubility and further examine the influence of solubility augmentation on their biological activities. We first developed and validated a simple, accurate RP HPLC-PDA method for detecting, measuring, and standardising the compounds in nanoformulations to achieve this wide goal. Efficient separation and quantification were carried out using Shim-pack GIST C18 (5 𝜇m 150 × 4.6 mm) column, maintained at 25 ℃ with isocratic elution using acetonitrile and acidified water (0.1% Trifluoracetic acid) (75:25 v/v) at 0.5 mL/min flow rate. The injection volume was 20 𝜇L, and eluents were detected at 333 nm at a retention time of 4.82 mins. Method validation was done following ICH guidelines. Results demonstrated that the method is specific, precise, and accurate within the recommended limits. The method showed good linearity with a 0.9994 correlation coefficient over a concentration range of 2.5-50 𝜇g/ml. The method efficiently detected and quantified the novel pyrazolone compound in the nanosuspension. The obtained nanoformulations PBC-PLGA 301 and PBC-PLGA 302 were characterised using various in vitro techniques. Size, PDI and ZP of the optimised nanoformulations were 166.6 ± 7.12 nm, 0.129 ± 0.042, -14.14 ± 2.90 mV for PBC-PLGA 301 and 192.5 ± 1.08 nm, 0.132 ± 0.025, -10.77 ± 1.515 mV for PBC-PLGA 302 with the encapsulation efficiency being 84.20 ± 0.930 and 81.5 ± 2.051, respectively. The compound release from the nanovesicles followed a sustained release pattern, with PBC-PLGA 301 and PBC-PLGA 302 attaining a cumulative release of approximately 37% and 53% in 48 hours. The biological activity assays showed a better-enhanced activity with the nanoformulations compared to the non-encapsulated PBC 301 and PBC-302. In vitro antibacterial activity revealed that the compound-loaded nanovesicles have better activity against the two gram-positive bacteria S. aureus and Methicillin-resistant S. aureus compared to the standard drug vancomycin and the non-encapsulated compound. On the other, the cell penetration assay further revealed that the compound-loaded nanovesicles achieved greater than 90% propidium iodide penetration (translating to cell death) at the reported MIC well for S. aureus while showing 86% and 89% cell penetration for Methicillin-resistant S. aureus. Also, the nanoformulations showed improved radical scavenging activity in a concentration-dependent manner, with PBC-PLGA 301 exhibiting the best antioxidant activity against DPPH, FRAP and nitric oxide compared to the standard antioxidant-gallic acid and the non-encapsulated compounds. In conclusion, the aqueous solubility of the two pyrazolone compounds, PBC-301 and PBC-302, was greatly enhanced by their encapsulation into a nanosystem, resulting in improved biological activities. Therefore, the nanoformulations of the pyrazolone-based derivatives can be exploited as potential pharmaceutical agents to fight bacterial infections and other diseases triggered by oxidative stress, cancer, and hepatic and vascular diseases. The data from this study has resulted in two first-authored research publications.Item Novel antimicrobial peptides for enhanced antimicrobial activity against methicillin resistant Staphylococcus aureus: design, synthesis and formulation.(2018) Faya, Andile Kennedy Mbuso.; Govender, Thirumala.Abstract available in pdf.