Programme: BIochemistry
Permanent URI for this collectionhttp://itsupport.cu.edu.ng:4000/handle/123456789/28779
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Item Targeting invasion-associated proteins PfSUB2 and PfTRAMP in Plasmodium falciparum: identification of potential inhibitors via molecular docking(BMC Infectious Diseases, 2025) Okafor, Esther. O.; Bella-Omunagbe, Mercy; Elugbadebo, Temitope; Dokunmu, Titilope M.; Adebiyi, EzekielPlasmodium falciparum subtilisin-like protease 2 (PfSUB2) is responsible for processing Plasmodium falciparum thrombospondin-related apical merozoite protein (PfTRAMP). These proteins are essential for asexual blood stage growth and RBC invasion and have, therefore, been identified as potential drug targets. This study predicted the three-dimensional structure of PfSUB2 and PfTRAMP and identified potential inhibitors using molecular docking methods. Five hundred nineteen compounds were docked against both proteins with AutoDock Vina in PyRx. Compounds 139,974,934 and 154,414,021 exhibited better binding affinities when compared to the standard inhibitors, PMSF, which highlights them as suitable inhibitors and potential antimalarials targeting PfTRAMP and PfSUB2. It also highlights 155,204,487 as a compound with dual antimalarial target potential, exhibiting a better binding affinity to PfTRAMP and PfSUB2. The study recommends 139,974,934, 154,414,021, and 155,204,487 as possible compounds for antimalarial drug development.Item Ex Vivo Molecular Studies and In Silico Small Molecule Inhibition of Plasmodium falciparum Bromodomain Protein 1(Drugs Drug Candidates, 2025-06-22) Oladejo, David O.; Dokunmu, Titilope M.; Oduselu, Gbolahan O.; Oladejo, Daniel O.; Ogunlana, Olubanke O.; Iweala, Emeka E. J.Background: Malaria remains a significant global health burden, particularly in sub- Saharan Africa, accounting for high rates of illness and death. The growing resistance to frontline antimalarial therapies underscores the urgent need for novel drug targets and therapeutics. Bromodomain-containing proteins, which regulate gene expression through chromatin remodeling, have gained attention as potential targets. Plasmodium falciparum bromodomain protein 1 (Pf BDP1), a 55 kDa nuclear protein, plays a key role in recognizing acetylated lysine residues and facilitating transcription during parasite development. Methods: This study investigated ex vivo PfBDP1 gene mutations and identified potential small molecule inhibitors using computational approaches. Malariapositive blood samples were collected. Genomic DNA was extracted, assessed for quality, and amplified using Pf BDP1-specific primers. DNA sequencing and alignment were performed to determine single-nucleotide polymorphism (SNP). Structural modeling used the PfBDP1 crystal structure (PDB ID: 7M97), and active site identification was conducted using CASTp 3.0. Virtual screening and pharmacophore modeling were performed using Pharmit and AutoDock Vina, followed by ADME/toxicity evaluations with SwissADME, OSIRIS, and Discovery Studio. GROMACS was used for 100 ns molecular dynamics simulations. Results: The malaria prevalence rate stood at 12.24%, and the sample size was 165. Sequencing results revealed conserved PfBDP1 gene sequences compared to the 3D7 reference strain. Virtual screening identified nine lead compounds with binding affinities ranging from −9.8 to −10.7 kcal/mol. Of these, CHEMBL2216838 had a binding affinity of −9.9 kcal/mol, with post-screening predictions of favorable drug-likeness (8.60), a high drug score (0.78), superior pharmacokinetics, and a low toxicity profile compared to chloroquine. Molecular dynamics simulations confirmed its stable interaction within the PfBDP1 active site. Conclusions: Overall, this study makes a significant contribution to the ongoing search for novel antimalarial drug targets by providing both molecular and computational evidence for PfBDP1 as a promising therapeutic target. The prediction of CHEMBL2216838 as a lead compound with favorable binding affinity, drug-likeness, and safety profile, surpassing those of existing drugs like chloroquine, sets the stage for preclinical validation and further structure-based drug design efforts. These findings are supported by prior experimental evidence showing significant parasite inhibition and gene suppression capability of predicted hits.Item Plasmodium falciparum Transketolase as a Drug Target in Malaria: A Review of Current Research and Future Perspectives(Journal of Science and Technology, Research Vol. 7, Special Issue: Landmark University International Conference, 2025) Orogun, Yetunde; Fadare, Olatomide; Bajepade, Tobilola; Raimi, Olawale; Ogunlana, OlubankeMalaria is a severe infectious disease caused by Plasmodium species, primarily Plasmodium falciparum, which accounts for the most deaths globally. Africa bears the heaviest malaria burden, with countries like Nigeria, Congo, and Mozambique contributing to a significant percentage of global cases. It is transmitted through the bite of an infected female Anopheles mosquito. The fight against malaria has been challenged by the emergence of resistance to most antimalarial drugs, including Artemisinin-based Combination Therapies (ACTs). This highlights the urgent need for novel drug targets. Transketolase (Tk), a key enzyme in the pentose phosphate pathway (PPP) non-oxidative branch, plays a vital role in cellular metabolism and has been identified to support parasite survival. Plasmodium falciparum transketolase (PfTk) has been identified as an emerging drug target due to its essential role in the parasite's metabolism and low structural homology with human transketolase (HTk). This review aims to provide an overview of PfTk as a potential anti-malarial drug target and to highlight the key research direction for future drug development. It examines the current research on PfTk as a therapeutic target, focusing on its biochemical properties, structural and functional characteristics, and potential inhibitors' development as a therapeutic strategy while exploring future perspectives.Item EVALUATION OF SYNTHETIC FLAVONOID BASED COMPOUNDS AS INHIBITORS OF Plasmodium falciparum TRANSKETOLASE(Covenant University Ota, 2025-09) OROGUN, Yetunde Grace; Covenant University DissertationMalaria, primarily attributed to Plasmodium falciparum, remains a significant contributor to global mortality, with Africa experiencing the greatest burden, particularly in countries such as Nigeria, the Democratic Republic of Congo, and Mozambique. The rise in resistance to present therapies, including Artemisinin-based Combination Therapies (ACTs), underscores the urgent need for novel drug targets. Transketolase, a thiamine-dependent enzyme in the non-oxidative arm of the pentose phosphate pathway, is vital for parasite metabolism and structurally distinct from the human enzyme, making it a promising selective target. Twenty synthetic flavonoid-based compounds were evaluated as potential inhibitors of P. falciparum transketolase (PfTk). Molecular docking revealed strong binding affinities, while ADMET profiling showed that most compounds complied with Lipinski’s rule. Notably, Compounds 6, 7, 11, and 13 were predicted to be orally bioavailable with favorable pharmacokinetic and drug-likeness properties. The compounds were further tested in vitro against PfTk and human transketolase (hTk), with oxythiamine as the positive control, and cytotoxicity was assessed using hemolysis assays on human red blood cells. The results demonstrated that several compounds exhibited high potency and selective inhibition of PfTk with minimal activity on hTk. Among them, Compounds 6, 7, and 10 emerged as the most promising leads, combining high selectivity, oral bioavailability, and favorable safety margins. Additionally, Compounds 11 and 13, analogues of Compound 10, showed good drug-likeness and oral bioavailability, indicating potential for structural optimization. Hemolysis assays confirmed minimal red blood cell lysis across all compounds, supporting their safety. In conclusion, this study validates PfTk as a viable drug target and identifies Compounds 6, 7, and 10 as strong lead candidates, with Compounds 11 and 13 as promising analogues for further optimization and development of safe, effective antimalarial agents.