In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.

Coronavirus Disease 2019 (COVID-19) Pandemic is ongoing, and to know how far the virus has spread in Niger State, Nigeria, a pilot study was carried out to determine the COVID-19 seroprevalence, patterns, dynamics, and risk factors in the state. A cross sectional study design and clustered-stratified-Random sampling strategy were used. COVID-19 IgG and IgM Rapid Test Kits (Colloidal gold immunochromatography lateral flow system) were used to determine the presence or absence of antibodies to SARS-CoV-2 in the blood of sampled participants across Niger State as from 26th June 2020 to 30th June 2020. The test kits were validated using the blood samples of some of the NCDC confirmed positive and negative COVID-19 cases in the State. COVID-19 IgG and IgM Test results were entered into the EPIINFO questionnaire administered simultaneously with each test. EPIINFO was then used for both the descriptive and inferential statistical analyses of the data generated. The seroprevalence of COVID-19 in Niger State was found to be 25.41% and 2.16% for the positive IgG and IgM respectively. Seroprevalence among age groups, gender and by occupation varied widely. A seroprevalence of 37.21% was recorded among health care workers in Niger State. Among age groups, COVID-19 seroprevalence was found to be in order of 30-41 years (33.33%) > 42-53 years (32.42%) > 54-65 years (30%) > 66 years and above (25%) > 6-17 years (19.20%) > 18-29 years (17.65%) > 5 years and below (6.66%). A seroprevalence of 27.18% was recorded for males and 23.17% for females in the state. COVID-19 asymptomatic rate in the state was found to be 46.81%. The risk analyses showed that the chances of infection are almost the same for both urban and rural dwellers in the state. However, health care workers and those that have had contact with person (s) that travelled out of Nigeria in the last six (6) months are twice ( 2 times) at risk of being infected with the virus. More than half (54.59%) of the participants in this study did not practice social distancing at any time since the pandemic started. Discussions about knowledge, practice and attitude of the participants are included. The observed Niger State COVID-19 seroprevalence means that the herd immunity for COVID-19 is yet to be achieved and the population is still susceptible for more infection and transmission of the virus. If the prevalence stays as reported here, the population will definitely need COVID-19 vaccines when they become available. Niger State should fully enforce the use of face/nose masks and observation of social/physical distancing in gatherings including religious gatherings in order to stop or slow the spread of the virus.

Understanding the evolution of antibiotic resistance at the molecular level as a functional tool for bioinformatic-based drug design.

The emergence of a drug resistant non-receptor tyrosine kinase (c-Src) in triple-negative breast cancer (TNBC) remains a prime concern in relation to the burden of TNBC among people living with breast cancer and drug development. Thr91 mutation was found to induce a complete loss of protein conformation required for drug fitness. Herein, we provide the first account of the molecular impact of the Thr91 mutation on c-Src resistance to experimental drug UM-164 using various computational approaches, namely molecular dynamics simulation, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, hydrogen bond occupancy, thermodynamics calculation, ligand-residue interaction and residue interaction networks (RINs). Findings from this study revealed that Thr91 mutation leads to a steric conflict between UM-164 and the side chain of methionine (Met91); this mutation distorts the UM-164 optimum orientation on the conformational space of mutant c-Src compared to the wild-type; decreases hydrogen bond formation between the residues in the mutant protein structure; decreases the UM-164 binding energy in the mutant by -13.416 kcal mol; reduces the residue correlation in the mutant protein structure; induces a change in the overall protein structure conformation from an inactive to active conformation; and distorts the ligand atomic interaction network and the residue interaction network. This report provides important insights that will assist in the further design of novel dual kinase inhibitors to minimise the chances of drug resistance in triple negative breast cancer.

This study provides the first account of the molecular impact of UM-164 binding on lyn protein using various computational approaches.

UM-164, a potent Src/p38 inhibitor, is a promising lead compound for developing the first targeted therapeutic strategy against triple-negative breast cancer (TNBC). However, lack of understanding of conformational features of UM-164 in complex with Src serves a challenge in the rational design of novel Src dual inhibitors. Herein, we provide an in-depth insight into conformational features of Src-UM-164 using different computational approaches. This involved molecular dynamics (MD) simulation, principal component analysis (PCA), thermodynamics calculations, dynamic cross-correlation (DCCM) analysis, and hydrogen bond formation. Findings from this study revealed that (1) the binding of UM-164 to Src induces a more stable and compact conformation; (2) the binding of UM-164 results in increased correlation among the active site residue; (3) the presence of multiple phenyl rings and fluorinated phenyl group in UM-164 contributes to the steric effect; (4) a relatively high-binding free energy estimated for the Src-UM-164 system is affirmative of its experimental potency; (5) hydrophobic packing contributes significantly to the drug binding in Src-UM-164; and (6) observed increase in H-bond distance of interacting residue atoms and Dasatinib compared to UM-164. Findings from this study can serve as a baseline in the design of novel Src inhibitors with dual inhibitory properties.

This is the thesis in which the chapters are written as a set of discrete research publications, with an overall introduction and final summary. Typically, these chapters will have been published in internationally recognized, peer-reviewed journals. This is to certify that the contents of this thesis are the original research work of Miss Ntombikayise Tembe.

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