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Author: search.filters.author.Covenant University DissertationSubject: search.filters.subject.Prostate cancer

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    VIRTUAL SCREENING OF PHTHALIMIDE-BASED INHIBITORS TO OVERCOME PROSTATE CANCER RESISTANT DRUGS
    (Covenant University, Ota, 2026-07) Ojo, Abigail Victory; Covenant University Dissertation
    Despite the successes of traditional androgen-deprivation therapy, the emergence of therapeutic resistance has become one of the main hurdles to PC management, and efforts have been made to develop novel molecules that inhibit the activity of persistent AR pathways. The aim of this work is to use a comprehensive in silico virtual screening approach to identify and assess phthalimide derivatives as potential inhibitors of the mutated androgen receptor protein (PDB ID: 1GS4). To find drug-like molecules, the initial library of 1508 phthalimide derivatives was retrieved from the PubChem database and structurally filtered using Lipinski's Rule of Five and an e-pharmacophore hypothesis phase module (Schrodinger) to remove non-drug-like molecules, resulting in 54 molecules. Using the high-throughput, extra-precision molecular docking and Molecular Mechanics-Generalized Born Surface Area free energy calculations, 13 compounds with binding affinities better than the clinical standard (Bicalutamide) were identified. Of these, 5-(1,3-dioxoisoindol-4-yl)-pentanenitrile was selected as the initial lead owing to its ADMET and excellent electronic properties, as determined by DFT calculations. The lead structure was then optimized to address toxicological issues associated with the CN and CO groups, yielding six new structural analogues of the lead compound. The best thermodynamic stability and binding were observed for Lead Analog A (4-heptyl-3-methoxyisoindolin-1-one), with a docking score of −10.742 kcal/mol. Critical pharmacokinetic profiling and toxicity studies demonstrated that this next-generation derivative not only has a greatly diminished risk of hepatotoxicity and mutagenic potential, but also exhibits high membrane permeability and blood-brain barrier penetration. Altogether, these computational results support a synergy between the optimized phthalimide scaffold and its observed potency, revealing a viable targeted therapeutic for prostate cancer that can overcome resistance.
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    ASSOCIATION OF COMT AND CYP1B1 POLYMORPHISMS WITH PROSTATE CANCER RISK IN NIGERIAN MEN
    (Covenant University Ota, 2025-09) Pirisola, Ayomikun Joshua; Covenant University Dissertation
    Prostate cancer (PCa) disproportionately affects men of African descent, with Nigeria recording high mortality rates, yet genetic studies in this population remain sparse. This study investigated the association between COMT rs4680 Val158Met, rs9332377, and CYP1B1 rs1056836 genetic variants and PCa risk and severity in Nigerian men. This case-control study involved 65 histologically confirmed PCa patients aged (median) 65 years old and 59 healthy controls aged (median) 60 years old. Genomic DNA was extracted from whole blood. Genotyping was conducted via TaqMan real-time PCR. Chi-square tests were conducted to compare genotype/allele frequencies, and associations were estimated using unadjusted logistic regression odds ratios (ORs) with 95% confidence intervals. Kruskal-Wallis tests and Spearman correlations were used to examine correlations with Gleason scores. Findings showed that there is a significant genotype and allele difference in COMT rs4680, where low-activity AA is the genotype that presents high risk (OR=9.50, 95% CI: 3.08-36.42, p<0.001 vs. GG), under genotypic as well as dominant models. In the case of rs9332377, the effect of the TT genotype showed a trend towards a protective effect but did not reach statistical significance (OR=0.21, 95% CI: 0.03-0.94, p=0.062 vs. CC). There were significant differences in CYP1B1 rs1056836, with the C alleles higher in cases (83.7% vs. 13.6%), and the GG risk being borderline (OR=4.074, p=0.056). None of the variants were significantly correlated with Gleason scores (p>0.05), although there was a trend in the case of rs1056836 (Spearman rho=0.263, p=0.089). These results suggest that genetic variation in COMT and CYP1B1 may contribute to PCa susceptibility among Nigerian men, potentially through impaired oestrogen detoxification pathways. Further validation in larger cohorts, with adjustments for environmental factors and comparisons across populations, is needed to clarify these associations.
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    ASSOCIATION OF IL6, TNF-α and IL10 POLYMORPHISM WITH PROSTATE CANCER RISK AND SEVERITY IN NIGERIAN MEN
    (Covenant University Ota, 2025-09) ALEEM, Adeola Abibat; Covenant University Dissertation
    One of the critical health burdens in Nigeria is prostate cancer (PCa) with high risk and death, especially men of African indigene. Persistent inflammation is influenced by soluble molecules such as interleukin-6 (IL6), tumor necrosis factor-alpha (TNFα), and interleukin-10 (IL10), which influences PCa development and malignancy, with single nucleotide polymorphisms (SNPs) in these genes influencing disease susceptibility and severity. This study investigated the association of IL6 (rs1800795), TNFα (rs1800629), and IL10 (rs1800872) SNPs with PCa risk and severity in a Nigerian cohort comprising 75 PCa victims and 81 healthy controls. Genotype and allele frequencies were determined using TaqMan SNP genotyping, and associations with PCa risk and severity (assessed via Gleason scores) were analysed. The results showed no statistical relationship between the studied SNPs and PCa risk. Specifically, rs1800629 showed a predominance of the GG genotype (85.7% cases, 86.4% controls) with a low minor allele frequency (MAF) for the A allele (7.04% cases, 6.72% controls; OR = 0.96, 95% CI: 0.39–2.38, p = 0.930), and no correlation with Gleason scores (p = 0.58). For rs1800872, genotype frequencies (TT: 14.3% cases, 16.9% controls; TG: 50.0% cases, 58.4% controls; GG: 35.7% cases, 24.7% controls). The minor T allele was less frequent in cases (39.3%) than in controls (46.1%), suggesting a protective effect, though the difference is not statistically significant. No meaningful associations was observed with PCa risk and the genotypes (OR = 1.711, GG vs. TT, p = 0.301; OR = 1.017, TG vs. TT, p = 0.971) or with Gleason scores (p = 0.95). Notably, rs1800795 exhibited complete monomorphism (GG genotype in all subjects), precluding its analysis as a biomarker for PCa risk or severity. The lack of significant associations may be attributed to population-specific genetic profiles, particularly the monomorphism of rs1800795 and low MAF of rs1800629, as well as the limited sample size, which constrained statistical power. These findings show the importance of population-specific genetic studies, as allele frequencies and their disease associations vary across populations. Future research should involve larger cohorts, genome-wide association studies, and functional analyses to explore other IL-6 SNPs, gene-environment interactions, and novel PCa-associated variants in Nigerians, contributing to improved molecular epidemiology and potential biomarkers for early diagnosis and targeted therapies in African populations.