Search results for: Tivani Phosa Mashamba-Thompson

Authors: Tivani Phosa Mashamba-Thompson, Mahmoud E. S. Soliman

Abstract:

To date, the cause of neurodegeneration is not well understood and diseases that stem from neurodegeneration currently have no known cures. Cathepsin B (CB) enzyme is known to be involved in the production of peptide neurotransmitters and toxic peptides in neurodegenerative diseases (NDs). CA-074Me is a membrane-permeable irreversible selective cathepsin B (CB) inhibitor as confirmed by in vivo studies. Due to the lack of the crystal structure, the binding mode of CA-074Me with the human CB at molecular level has not been previously reported. The main aim of this study is to gain an insight into the binding mode of CB CA-074Me to human CB using various computational tools. Herein, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition analysis were employed to accomplish the aim of the study. Another objective was to identify novel CB inhibitors based on the structure of CA-074Me using fragment based drug design using scaffold hoping drug design approach. Results showed that two of the designed ligands (hit 1 and hit 2) were found to have better binding affinities than the prototype inhibitor, CA-074Me, by ~2-3 kcal/mol. Per-residue energy decomposition showed that amino acid residues Cys29, Gly196, His197 and Val174 contributed the most towards the binding. The Van der Waals binding forces were found to be the major component of the binding interactions. The findings of this study should assist medicinal chemist towards the design of potential irreversible CB inhibitors.

Keywords: cathepsin B, scaffold hopping, docking, molecular dynamics, binding-free energy, neurodegerative diseases

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Authors: Ncoza Dlova, Tivani Mashamba-Thompson

Abstract:

Garcinia livingstonei (Clusiaceae) extracts, morelloflavone- 7″- sulphate and sargaol were shown to be effective against hyper-pigmentation through inhibition of tyrosinase enzyme, in vitro . The aim of this study is to elucidate the structural mechanism through which morelloflavone- 7″- sulphate and sargaol binds human tyrosinase. Implementing a homology model to construct a tyrosinase model using the crystal structure of a functional unit from Octopus hemocyanin (PDB: 1JS8) as a reference template enabled us to create a human tyrosinase model. Molecular dynamics and binding free energy calculations were optimized to enable molecular dynamics simulation of the copper dependent inhibitors. Results show the importance of the hydrogen bond formation morelloflavone- 7″- sulphate and sargaol between compound and active site residues. Both complexes demonstrated the metallic coordination between compound and arginine residue as well as copper ions within the active site. The comprehensive molecular insight gained from this study should be vital in understanding the binding mechanism morelloflavone- 7″- sulphate and sargaol. Moreover, these results will assist in the design of novel of metal ion dependent enzyme inhibitors as potential anti-hyper-pigmentation disorder therapies.

Keywords: hyper-pigmentation disorders, dyschromia African skin, morelloflavone- 7″- sulphate, sagoal

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Authors: Neusa Fernanda Torres, Buyisile Chibi, Lyn E. Middleton, Vernon P. Solomon, Tivani P. Mashamba-Thompson

Abstract:

Background: Self-medication with antibiotics (SMA) is a global concern, with a higher incidence in low and middle-income countries (LMICs). Despite intense world-wide efforts to control and promote the rational use of antibiotics, continuing practices of SMA systematically exposes individuals and communities to the risk of antibiotic resistance and other undesirable antibiotic side effects. Moreover, it increases the health systems costs of acquiring more powerful antibiotics to treat the resistant infection. This review thus maps evidence on the factors influencing self-medication with antibiotics in these settings. Methods: The search strategy for this review involved electronic databases including PubMed, Web of Knowledge, Science Direct, EBSCOhost (PubMed, CINAHL with Full Text, Health Source - Consumer Edition, MEDLINE), Google Scholar, BioMed Central and World Health Organization library, using the search terms:’ Self-Medication’, ‘antibiotics’, ‘factors’ and ‘reasons’. Our search included studies published from 2007 to 2017. Thematic analysis was performed to identify the patterns of evidence on SMA in LMICs. The mixed method quality appraisal tool (MMAT) version 2011 was employed to assess the quality of the included primary studies. Results: Fifteen studies met the inclusion criteria. Studies included population from the rural (46,4%), urban (33,6%) and combined (20%) settings, of the following LMICs: Guatemala (2 studies), India (2), Indonesia (2), Kenya (1), Laos (1), Nepal (1), Nigeria (2), Pakistan (2), Sri Lanka (1), and Yemen (1). The total sample size of all 15 included studies was 7676 participants. The findings of the review show a high prevalence of SMA ranging from 8,1% to 93%. Accessibility, affordability, conditions of health facilities (long waiting, quality of services and workers) as long well as poor health-seeking behavior and lack of information are factors that influence SMA in LMICs. Antibiotics such as amoxicillin, metronidazole, amoxicillin/clavulanic, ampicillin, ciprofloxacin, azithromycin, penicillin, and tetracycline, were the most frequently used for SMA. The major sources of antibiotics included pharmacies, drug stores, leftover drugs, family/friends and old prescription. Sore throat, common cold, cough with mucus, headache, toothache, flu-like symptoms, pain relief, fever, running nose, toothache, upper respiratory tract infections, urinary symptoms, urinary tract infection were the common disease symptoms managed with SMA. Conclusion: Although the information on factors influencing SMA in LMICs is unevenly distributed, the available information revealed the existence of research evidence on antibiotic self-medication in some countries of LMICs. SMA practices are influenced by social-cultural determinants of health and frequently associated with poor dispensing and prescribing practices, deficient health-seeking behavior and consequently with inappropriate drug use. Therefore, there is still a need to conduct further studies (qualitative, quantitative and randomized control trial) on factors and reasons for SMA to correctly address the public health problem in LMICs.

Keywords: antibiotics, factors, reasons, self-medication, low and middle-income countries (LMICs)

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