Department of Chemistry

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Author: search.filters.author.Covenant University DissertationHas files: Yes

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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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    IN SILICO IDENTIFICATION OF POTENTIAL Plasmodium falciparum ACETYL-COA SYNTHETASE (PfACS) INHIBITORS USING DRUG REPURPOSING APPROACH
    (Covenant University, Ota, 2026-06) Akinwale, Oluwapelumi Lois; Covenant University Dissertation
    The persistent rise in malaria-related deaths among children and pregnant women underscores the ongoing global health challenge posed by this disease. Although preventive activities and first-line treatment options (which include artemisinin-based combination therapies) have been extensively used, the swift development of drug-resistant Plasmodium falciparum isolates has left malaria control efforts severely impaired. Drug repurposing provides an economical alternative to traditional drug discovery approaches by uncovering novel therapeutic uses for existing drugs with well-characterized safety profiles. This study focuses on Plasmodium falciparum acetyl-CoA synthetase (PfACS), an essential enzyme involved in acetate metabolism and histone acetylation, as a potential antimalarial drug target. Its structural divergence from human isoforms increases its likelihood of selective inhibition, with the lowest potential to induce toxicity in the host. A multistage computational drug repurposing workflow was employed to identify FDA-approved inhibitors of PfACS. Structural analysis identified the crystal structure of Coccidioides immitis acetyl-CoA synthetase (PDB: 7KQ6) as the most suitable template for PfACS modeling. The AlphaFold2-predicted PfACS structure was also validated. A library of 12,718 DrugBank compounds was sequentially selected using Lipinski’s Rule of Five and the Ersilia eos80ch machine-learning antiplasmodial activity model, yielding a dataset of 377 biologically enriched compounds. Molecular docking, binding free-energy estimation (MM/GBSA), pharmacophoric interaction analysis, and density functional theory (DFT) calculations and Molecular Dynamics (MD) Simulation were subsequently performed. Four lead compounds (Hit 01–04) demonstrated favorable binding affinity, interaction similarity with the reference inhibitor MMV693183, and supportive electronic reactivity profiles, with promising potential as PfACS inhibitors and antimalarial agents.