Browsing by Author "Egieyeh, Samuel"
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Item Cheminformatic Approaches to Hit-Prioritization and Target Prediction of Potential Anti-MRSA Natural Products(University of the Western Cape, 2020) Oselusi, Samson Olaitan; Egieyeh, SamuelThe growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates. Cheminformatic approaches in drug discovery enable chemical data mining, in conjunction with unsupervised and supervised learning from available bioactivity data that may unlock the full potential of NPs in antimicrobial drug discovery. Therefore, taking advantage of the available NPs with their known in vitro activity against MRSA, this study conducted cheminformatic and data mining analysis towards hit profiling, hit-prioritization, hit-optimization, and target prediction of anti-MRSA NPs. Cheminformatic profiling was conducted on the 111 anti-MRSA NPs (AMNPs) retrieved from literature. About 20 current drugs for MRSA (CDs) were used as a reference to identify AMNPs with promising prospects to become drug candidates.Item Cheminformatic approaches to hit-prioritization and target prediction of potential anti-mrsa natural products(University of Western Cape, 2020) Oselusi, Samson Olaitan; Egieyeh, Samuel; Christoffels, AlanThe growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates.Item Exploration of scaffolds from natural products with antiplasmodial activities, currently registered antimalarial drugs and public malarial screen data(MDPI, 2016) Egieyeh, Samuel; Syce, James; Christoffels, Alan; Malan, Sarel F.In light of current resistance to antimalarial drugs, there is a need to discover new classes of antimalarial agents with unique mechanisms of action. Identification of unique scaffolds from natural products with in vitro antiplasmodial activities may be the starting point for such new classes of antimalarial agents. We therefore conducted scaffold diversity and comparison analysis of natural products with in vitro antiplasmodial activities (NAA), currently registered antimalarial drugs (CRAD) and malaria screen data from Medicine for Malaria Ventures (MMV). The scaffold diversity analyses on the three datasets were performed using scaffold counts and cumulative scaffold frequency plots. Scaffolds from the NAA were compared to those from CRAD and MMV. A Scaffold Tree was also generated for each of the datasets and the scaffold diversity of NAA was found to be higher than that of MMV. Among the NAA compounds, we identified unique scaffolds that were not contained in any of the other compound datasets. These scaffolds from NAA also possess desirable drug-like properties making them ideal starting points for antimalarial drug design considerations. The Scaffold Tree showed the preponderance of ring systems in NAA and identified virtual scaffolds, which may be potential bioactive compounds.Item Feasibility of an internationally recognized conformitè europëenne equivalent mark for medical devices in africa: a review of current literature(University of the Western cape, 2024) Nkuku, Khanyisile Zachia; Egieyeh, SamuelMedical devices are crucial to health systems and are critical to addressing the disease burden of African countries. In light of the importance of diagnosis and surgical intervention in healthcare, medical devices such as radiation emitting devices and devices incorporating a substance, are held to a high standard of quality and safety. Hence, the regulation of medical devices is required to optimize their use in healthcare within Africa. To successfully transition from the existing unregulated medical device sector to a thorough regulatory framework, many nations lack both the financial and technological resources. Consequently, organizations attempting to manufacture and market medical devices confront numerous obstacles, such as navigating the regulatory frameworks of various other nations and creating sustainable business models for imported medical devices. Many nations, including countries in Africa such as South Africa, Nigeria, and Ghana, require Conformitè Europëenne (CE) marked products which can only be obtained in Europe, making it extremely costly for local African manufacturers of medical devices to bring their products onto the market in these African countriesItem Feasibility of an internationally recognized conformitè europëenne equivalent mark for medical devices in Africa: a review of current literature(Universty of the Western Cape, 2024) Nkuku, Khanyisile Zachia; Egieyeh, SamuelMedical devices are crucial to health systems and are critical to addressing the disease burden of African countries. In light of the importance of diagnosis and surgical intervention in healthcare, medical devices such as radiation emitting devices and devices incorporating a substance, are held to a high standard of quality and safety. Hence, the regulation of medical devices is required to optimize their use in healthcare within Africa. To successfully transition from the existing unregulated medical device sector to a thorough regulatory framework, many nations lack both the financial and technological resources. Consequently, organizations attempting to manufacture and market medical devices confront numerous obstacles, such as navigating the regulatory frameworks of various other nations and creating sustainable business models for imported medical devices. Many nations, including countries in Africa such as South Africa, Nigeria, and Ghana, require Conformitè Europëenne (CE) marked products which can only be obtained in Europe, making it extremely costly for local African manufacturers of medical devices to bring their products onto the market in these African countries. This study examined the feasibility of establishing an African-based equivalent of Conformitè Europëenne mark (CE mark) with a similar standard to that in Europe for indigenous African medical device manufacturers. The study also explored how such African-based CE mark will encourage innovation and expand access to medical devices in Africa.Item Homology modelling and characterization of three-dimensional (3d) protein structures of selected variants of cyp3a4(University of the Western Cape, 2022) Omotoso, Christianah Taye; Egieyeh, SamuelThe efficacy and toxicity of several drugs and prodrugs are influenced by the interindividual genetic variations in drug-metabolising enzymes. Cytochrome P450 enzymes constitute the major metabolising enzymes in humans. Cytochrome 3A4 (CYP3A4) is the highest abundantly expressed human cytochrome P450 enzyme metabolising about 40% of marketed drugs. Several studies have shown the significant effects of CYP3A4 single nucleotide variability on its enzymatic activity and the pharmacokinetic parameters of metabolized drugs. However, there is a paucity of information on the molecular characteristics (including threedimensional protein structures, physicochemical properties, and molecular dynamics characteristics) of single nucleotide variants of CYP3A4 enzymes that may be correlated with the reported variability of their enzymatic activities.Item Identification of potential antibiofilm hit compounds from two African natural product database against multi-drug resistant staphylococcus aureus: an in silico study(University of the Western Cape, 2023) Ilori, Tosin Lydia; Egieyeh, SamuelOne of the crucial ways by which Staphylococcus aureus develops resistance to antibiotics is biofilm formation, a protective mechanism involving extracellular polymeric substance (EPS) matrix that shields microorganisms from the effects of antibiotics, mechanical forces, pH, and host immune responses. While some encouraging results point to the possible use of FDA-approved medications against biofilms, more research is needed due to sporadic and patchy data. The complex chemical diversity of natural compounds makes them a reservoir of bioactive molecules for drug discovery. This study seeks to identify effective potential antibiofilm compounds from a query dataset compiled from two African natural product databases (SANCDb and AfroDb). A database of known antibiofilm compounds was created from ChEMBL, PubChem, and other related databases while a query dataset of natural products was compiled for this study. The ligand similarity (LS) searches were unable to unequivocally identify distinct differences in the molecular structures and functional group moiety of the active and inactive compounds.Item Knowledge, perceptions and practices of risk-based monitoring among clinical practitioners in the United States(University of the Western Cape, 2018) Hockin, Jennifer; Egieyeh, SamuelThis study investigated the current knowledge, perceptions, and practices of Risk-Based Monitoring (RBM) using written and verbal responses to an ethics review board approved questionnaire. Responses were collected from individuals involved in the practice, oversight, and implementation of clinical trial monitoring in the USA. RBM was viewed as a positive force with a bright future. However the results suggested that a renewed focus on change management strategies is needed to ensure RBM practices penetrate all levels of clinical trial management. The site sponsor/site operational relationship was identified as a key RBM component. Shortcomings in this relationship were identified as significant operational barriers to effective RBM practice. Respondents indicated that current RBM training efforts were lacking. Because RBM is new and its practices deviate significantly from the past total monitoring efforts, both industry and the clinic need to work harder to ensure that everyone involved in clinical trial monitoring understands these differences. Fortunately, overcoming the identified barriers will not require massive changes to current RBM practice. By refocusing efforts on the sponsor/CRO and investigative sites to attain RBM governance, develop quality control plans, institute an optimal RBM platform, and improve training, the true promise of RBM is within reach. Each of these are critical pieces to an effective RBM implementation methodology and correcting initial stumbles in their implementation can assure the RBM future is as promised.Item A perspective on nanotechnology and covid-19 vaccine research and production in south africa(MDPI, 2021) Egieyeh, Samuel; Dube, AdmireAdvances in nanotechnology have enabled the development of a new generation of vaccines, which are playing a critical role in the global control of the COVID-19 pandemic and the return to normalcy. Vaccine development has been conducted, by and large, by countries in the global north. South Africa, as a major emerging economy, has made extensive investments in nanotechnology and bioinformatics and has the expertise and resources in vaccine development and manufacturing. This has been built at a national level through decades of investment. In this perspective article, we provide a synopsis of the investments made in nanotechnology and highlight how these could support innovation, research, and development for vaccines for this disease. We also discuss the application of bioinformatics tools to support rapid and cost-effective vaccine development and make recommendations for future research and development in this area to support future health challenges.Item Predictive classifier models built from natural products with antimalarial bioactivity using machine learning approach(Public Library of Science, 2018) Egieyeh, Samuel; Syce, James; Malan, Sarel F.; Christoffels, AlanIn view of the vast number of natural products with potential antiplasmodial bioactivity and cost of conducting antiplasmodial bioactivity assays, it may be judicious to learn from previous antiplasmodial bioassays and predict bioactivity of these natural products before experimental bioassays. This study set out to harness antimalarial bioactivity data of natural products to build accurate predictive models, utilizing classical machine learning approaches, which can find potential antimalarial hits from new sets of natural products. Classical machine learning approaches were used to build four classifier models (Naïve Bayesian, Voted Perceptron, Random Forest and Sequence Minimization Optimization of Support Vector Machines) from bioactivity data of natural products with in-vitro antiplasmodial activity (NAA) using a combination of the molecular descriptors and two-dimensional molecular fingerprints of the compounds. Models were evaluated with an independent test dataset. Possible chemical features associated with reported antimalarial activities of the compounds were also extracted. From the results, Random Forest (accuracy 82.81%, Kappa statistics 0.65 and Area under Receiver Operating Characteristics curve 0.91) and Sequential Minimization Optimization (accuracy 85.93%, Kappa statistics 0.72 and Area under Receiver Operating Characteristics curve 0.86) showed good predictive performance for the NAA dataset. The amine chemical group (specifically alkyl amines and basic nitrogen) was confirmed to be essential for antimalarial activity in active NAA dataset. This study built and evaluated classifier models that were used to predict the antiplasmodial bioactivity class (active or inactive) of a set of natural products from interBioScreen chemical library.Item Progress in pharmacometrics implementation and regulatory integration in Africa: A systematic review(John Wiley and Sons Inc, 2024) Ndzamba, Bonginkosi S'fiso; Egieyeh, Samuel; Fasinu, PiusThe availability of clinical trial data, advocacy, and increased funding has facilitated the implementation of pharmacometrics in Africa, resulting in the establishment of additional training programs for pharmacometricians. This study conducted a systematic review to evaluate the progress made from the implementation of pharmacometrics in clinical drug development and its adoption into drug approval by regulatory authorities in Africa. We performed a comprehensive literature search using major databases such as PubMed and Google Scholar. The study included articles published until 2024, with no lower cutoff. Articles were excluded if not addressing the research question or of pharmacometrics studies done outside Africa with no collaboration with African researchers (study setting). For the review, a total of 121 articles were included for analysis. Among the reported pharmacometrics approaches, Population pharmacokinetics modeling approaches are the most used (95 (78.5%)). South Africa and Uganda researchers have the most research output in pharmacometrics in Africa (82 (89.1%) and 7 (7.61%), respectively), with the University of Cape Town (South Africa) producing the highest (71 (78.8%)) of all article in Africa. The most studied conditions are TB (43 (35.5%)), HIV (33 (27.3%), TB and HIV (22 (18.2%)), and malaria (12 (9.92%). Pharmacometrics is gaining momentum in Africa, and the progress made since inception will significantly improve the safety and efficacy of therapeutic agents used to treat HIV, TB, and other emerging conditions.Item Selection, synthesis and evaluation of novel drug-like compounds from a library of virtual compounds designed from natural products with antiplasmodial activities(University of the Western Cape, 2020) Pokomi, Rostand Fankam; Joubert, Jacques; Malan, Sarel; Egieyeh, SamuelMalaria is an infectious disease which continues to kill more than one million people every year and the African continent accounts for most of the malaria death worldwide. New classes of medicine to combat malaria are urgently needed due to the surge in resistance of the Plasmodium falciparum (the parasite that causes malaria in humans) to existing antimalarial drugs. One approach to circumvent the problem of P. falciparum resistance to antimalarial drugs could be the discovery of novel compounds with unique scaffolds and possibly new mechanisms of action. Natural products (NP) provide a wide diversity of compounds with unique scaffolds, as such, a library of virtual compounds (VC) designed from natural products with antiplasmodial activities (NAA) can be a worthy starting point.Item Structure-Based Virtual Screening of Selected Malaria Box Compounds Against a Multi-Staged Protein (Falstatin) in Plasmodium falciparum(University of the Western Cape, 2021) Oladunjoye, Bolu Bimbola; Egieyeh, SamuelMalaria disease poses substantial health risks to many nations, especially in Africa, where it primarily affects pregnant women, children, and immunocompromised patients. However, current antimalarial drugs have limitations such as low safety profile and particularly widespread treatment failure due to the increasing resistance of Plasmodium falciparum, the major causative organism to artemisinin-based therapy (ACT) and other chemotherapeutics. In the light of this, there is a pressing need for new antimalarial drugs with novel mechanisms of action and satisfactory pharmacokinetic properties, which has led to the current study. Furthermore, current antimalarial drugs target specific stages of the Plasmodium life cycle. For instance, chloroquine targets the erythrocytic stage while primaquine targets the liver stage. However, these therapies cannot achieve complete elimination of the parasite once the life cycle has been established in the body. Hence, the goal of this study is to combat resistance by finding novel compounds that can bind to a multiple-staged protein in Plasmodium falciparum. Based on this consideration, falstatin was chosen as the protein target for this study because it was observed to play a crucial role in the degradation of haemoglobin, rupture of erythrocytes by mature schizonts, and subsequent invasion of erythrocytes by free merozoites. Hence, the protein, falstatin can be targeted to inhibit cell growth and cause plasmodial cell death in merozoites as well as schizonts of Plasmodium falciparum. Therefore, it is intended that compounds that bind to falstatin could serve as novel antimalarials that target multiple stages of the Plasmodium life cycle. Consequently, this study explored the structure-based virtual screening approach to identify compounds that could bind to the protein target, falstatin in Plasmodium falciparum. An extensive literature review identified falstatin as the multi-staged drug target for this study, while homology modelling was used to generate the three-dimensional structure of falstatin. Molecular docking was conducted to predict the binding energy of compiled antiplasmodial compounds to falstatin while druglikeness analysis was used to prioritize compounds according to their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. The top-ranked compound, based on a novel ligand scoring function, was then subjected to molecular dynamics (MD). Following this step, rescoring analysis was performed on the top 5 compounds using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring function to gain insight into their component binding energies. Thereafter, a pharmacophore hypothesis was developed based on the 5 top-ranking compounds in order to screen other compound libraries in the future. From the results, TCMDC 131646, TCMDC-124274, TCMDC-138266, TCMDC 123844 and TCMDC 131234 possessed good binding energies and satisfactory ADMET properties showing high ligand scores of 77.1, 75.4, 75.4, 75.4 and 73.1 respectively (on a total scale of 100). Also, the study revealed that the top-ranked compound, TCMDC 131646 had a binding energy of -6.15 KJ/mol, contained no toxicophore and conformed to Lipinski, Egan and Muegge rules of druglikeness. Findings from the MD simulation demonstrated that TCMDC 131646 strongly interacted with the protein, falstatin. Morealso, the study revealed that TCMDC 131646 is structurally diverse from chloroquine, artemisinin, artemether and lumefantrine, indicating that it may possess a distinct mechanism of action. The rescoring analysis of TCMDC-131646, TCMDC 124274, TCMDC-138266, TCMDC 123844 and TCMDC 131234 predicted negative binding energies ≤ -4.662 KJ/mol for the top compounds, further indicating that these compounds are likely to bind strongly with falstatin. Additionally, the developed pharmacophore hypothesis contained -H-N-C=O and N-H moieties which strongly suggested that the presence of electron-withdrawing groups could be vital for the inhibition of falstatin at the active site. Overall, TCMDC 131646 was predicted to be a drug-like and safe compound that could inhibit falstatin in Plasmodium falciparum. Chemical-disease co-occurrence analysis in literature revealed that this compound showed in-vitro antiplasmodial activity at an IC50 of 0.226μM and has also shown in vitro activity for neuralgia, hyperalgesia and arthritis. The research recommends TCMDC 131646 as a potential antimalarial hit compound that could yield novel analogues by hit expansion. However, confirmatory in-vitro and in-vivo studies are required to substantiate these predictionsItem The transition of regulatory services from drug regulatory unit to Botswana medicines regulatory authority: an evaluation of the changes in regulatory services from the industry’s perspective(University of the Western Cape, 2023) Maloisane, Rebecca M; Egieyeh, Samuel; Gwaza, LutherThe Drug Regulatory Unit (DRU) was established by the Ministry of Health (MoH) to enforce the Drugs and Related Substances Act of 1992 in line with the Botswana National Drug Policy (BNDP) adopted in 2002 and the National Health Policy (NHP) to attain health for all. However, as with many National Regulation Authorities (NRAs) in low and middle-income countries, the DRU had major challenges in inefficient legislation and regulation to address the supply of substandard and falsified medicines, and financial and human resource constraints to maintain and sustain regulatory oversight. The Government of Botswana through the MoH restructured DRU into a semi-autonomous regulatory body, Botswana Medicines Regulatory Authority (BOMRA). To aid the NRAs in building and strengthening regulatory systems' capacity to regulate medicinal products effectively and efficiently, the World Health Organization (WHO) has generated a Global Benchmarking Tool (GBT) for member states. As of December 2019, a total of 26 countries underwent formal benchmarking while 54 countries including Botswana completed self-assessments using the WHO-GBT. Despite this self-assessment, there might be a need to assess the efficiency of the regulatory service delivery of BOMRA from the industry’s perspective. The study aimed to assess and compare the changes in the regulatory system for the WHO-recommended regulatory functions and service delivery following the transition of DRU to BOMRA from the industry’s perspective.