Programme: Industrial Chemistry

Permanent URI for this collectionhttp://itsupport.cu.edu.ng:4000/handle/123456789/28781

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Structure-based Design of Coumarin Moieties as Sustainable Inhibitors of Diabetes Mellitus Type 2
(2025) Opebiyi, O. T.; Oduselu, G.O.; Ogunnupebi, T. A.; Elebiju, O. F.; Adekoya, Joseph Adeyemi; Ajani, O. O.
The search for novel and more potent antidiabetic agents globally is due to the increase in insulin resistance, and more type 2 diabetes patients become susceptible to secondary compilations. Many pharmacologically active compounds are organic, mostly heterocyclic compounds, accounting for about 85% of Food and Drug Administration (FDA)-approved drugs. An example of a heterocyclic compound is coumarin, a benzopyrone group containing oxygen heteroatoms. Coumarin has been reported to possess several pharmacological properties, and combining coumarin with other compounds has made coumarin more potent. Computer-aided techniques have helped improve the design of potential drug candidates. Using computer-aided techniques, coumarin moieties were investigated for antidiabetic activities for future drug design. Coumarin template was used to search for ligand library on PubChem, an open chemistry database at the National Institutes of Health (NIH); 1653 compounds were downloaded with acarbose and metformin in SDF format, 1632 compounds, acarbose and metformin were successfully prepared, and then docked against human pancreatic alpha-amylase (Protein Data Bank- PDB ID: 4GQR) with Autodock vina. The qualitative structural assessment of the best hits from this molecular docking of a ligand library, acarbose and metformin was done. The functional groups present in this best hits, acarbose and metformin were used to generate 15 novel coumarin derivatives. The designed compounds were also docked against 4GQR, and their chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted. It was observed that 11 of the designed compounds had the lowest binding affinity than the co-crystalized ligand of 4GQR. The best hits compounds from the docking studies were 2g, 2f, 1a and 3e, and the ADMET studies predicted that compounds 1a, 3b, 3c and 3a had better pharmacokinetic and toxicity profiles. This promising result suggests that the designed compounds, particularly 1a, 3b, 3c and 3a, have the potential to be further optimized, synthesized and developed as potent antidiabetic agents, offering a hopeful future for diabetes treatment.
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.