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Author: search.filters.author.Dokunmu, Titilope M.Subject: search.filters.subject.Plasmodium falciparum

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    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, Ezekiel
    Plasmodium 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.
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    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.