Discovery Of Agents Research Articles

EvaluationMaster: A GUI Tool for Structure-Based Virtual Screening Evaluation Analysis and Decision-Making Support.

Structure-based virtual screening (SBVS) plays an indispensable role in the early phases of drug discovery, utilizing computational docking techniques to predict interactions between molecules and biological targets. During the SBVS process, selecting appropriate target structures and screening algorithms is crucial, as these choices significantly shape the outcomes. Typically, such selections require researchers to be proficient with multiple algorithms and familiar with evaluation and analysis processes, complicating their tasks. These algorithms' lack of graphical user interfaces (GUIs) further complicates it. To address these challenges, we introduced EvaluationMaster, the first GUI tool designed specifically to streamline and standardize the evaluation and decision-making processes in SBVS. It supports four docking algorithms' evaluation under multiple target structures and offers a comprehensive platform that manages the entire workflow─including the downloading of molecules, construction of decoy datasets, prediction of protein pockets, batch docking, and extensive data analysis. By automating complex evaluation tasks and providing clear visualizations of analysis results, EvaluationMaster significantly reduces the learning curve for researchers and boosts the efficiency of evaluations, potentially improving SBVS hit rates and accelerating the discovery and development of new therapeutic agents.

Network Pharmacology and In Silico Elucidation of Phytochemicals Extracted from Ajwa Dates (Phoenix dactylifera L.) to Inhibit Akt and PI3K Causing Triple Negative Breast Cancer (TNBC).

About 10-15% of all breast cancers comprise triple-negative breast cancer (TNBC), defined as cancer cells that lack receptors for the ER, PR, and HER2 protein receptors. Due to the absence of these receptors, treating TNBC using conventional chemotherapy is challenging and, therefore, requires the discovery of novel chemotherapeutic agents derived from natural sources. The current work was intended to study the potential phytochemicals of Ajwa dates (Phoenix dactylifera L.) with the predicted potential targets (namely, Akt and PI3K) to determine possible TNBC inhibitors. We harnessed network pharmacology, molecular docking, drug-likeness studies, Molecular Dynamics (MD) simulation, and binding free energy (MM-GBSA) calculation to get phytochemicals with potential effects against TNBC. Firstly, molecular docking was performed on 125 phytochemicals against the Akt and PI3K proteins utilizing PyRx. Then, the phytochemicals with the highest binding affinity (≤ -8.1 kcal/mol) were examined for in silico drug-likeness and toxicity profiles. Finally, phytochemicals with optimal druglikeness and toxicity profiles were studied by Molecular Dynamics (MD) simulation and binding free energy (MM-GBSA) to identify compounds that can form stable complexes. The results of the network pharmacology revealed that the Akt and PI3K proteins are potential targets of TNBC for the phytochemicals of Phoenix dactylifera L. used in this study. The outcomes of molecular docking displayed that among 125 phytochemicals, 42 of them (with a binding affinity ≤ -8.1 kcal/mol) have potentially inhibiting effects on both proteins PI3K and Akt expressed in TNBC. Then, the results of in silico drug-likeness identified seven phytochemicals with optimal pharmacokinetic profiles. Furthermore, toxicity studies showed that three phytochemicals (namely, Chrysoeriol, Daidzein, and Glycitein) did not cause any toxicities. Finally, the Molecular Dynamics (MD) simulation studies and binding free energy (MM-GBSA) verified that Daidzein stayed within the binding cavities of both proteins (Akt and PI3K) by establishing a stable protein-ligand complex during simulation. Taken together, the current work emphasizes the potential effects of Daidzein from Phoenix dactylifera L. against TNBC, and it can be further studied to establish it as a standard chemotherapy for TNBC.

Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor α-Positive Breast Cancer.

Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% of breast cancer cases, whose predominant treatment is currently endocrine therapy. The main strategy of endocrine therapy for ERα+ breast cancer is to inhibit the ERα signaling pathway and downregulate ERα levels, which often results in mutations in the ligand-binding domain (LBD) of ERα, leading to significant resistance to subsequent treatment in patients. To combat drug resistance, we first proposed a novel aptamer PROTAC strategy through specifically targeted degradation of ERα via targeting the DNA-binding domain (DBD) of ERα. We proved that this strategy is capable of targeting ERα for degradation through ubiquitination, leading to the inhibition of proliferation in ERα+ breast cancer cells and tamoxifen-resistant breast cancer cells. Furthermore, we investigated the mechanisms involved in overcoming resistance. By circumventing drug resistance associated with LBD mutations in ERα, our approach provides a promising avenue for the discovery of new therapeutic agents.

Abstract IA007: Preclinical Approaches to Discovery and Development of Novel Combination Therapies

Drug combinations provide an important tool to address the complexity of tumor biology, and the ability to drive deeper and more durable responses has led to many successful combination regimens in clinical use today. There are more possible novel combination regimens than can be feasibly explored clinically, and preclinical studies have become a common tool to identify and prioritize combinations partners for clinical investigation. Historically, these approaches have focused heavily on identification of synergy, however, a growing body of research is beginning to indicate that synergy may not be a key predictor of clinical utility. To better understand the role of synergy in combinations, we experimentally explored acquired resistance to combination therapies in preclinical models, and counterintuitively, find that combinations which derive activity through synergy rather than additivity can lead to less undesirable outcomes. Specifically, we find that the combinations which rely on synergy are more likely to develop resistance as well as demonstrate greater loss of combination activity upon acquisition of resistance than an equally active additive combination. We propose that instead of relying on synergy for combinations discovery, that a framework based on the 5Rs can be employed which emphasizes a more holistic view of combination rationale, development, and proposed clinical utility. We demonstrate the application of these principles to discovery of novel therapeutic agents in analysis of a large-scale pan-tumor screen, and how these factors can be used to identify novel rational combination partners linked to specific disease segments which drive activity in vivo. As more agents with novel mechanisms enter clinical development, preclinical studies will play an increasingly important role in designing combination regimens which can attack the tumor from multiple angles, leading to better activity, and present a more favorable therapeutic index. Citation Format: Jerome T. Mettetal Preclinical Approaches to Discovery and Development of Novel Combination Therapies. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA007

Computational and Experimental Insights into Pharmacological Potential: Synthesis, In Vitro Evaluation, and Molecular Docking Analysis of Bioactive Urea and Thiourea Derivatives.

This study delves into the synthesis, in vitro assessment, and molecular docking analysis of bioactive urea and thiourea derivatives, which have gained attention in pharma chemistry due to their versatile chemical reactivity and potential therapeutic applications. One pot synthetic methodology was employed to create a diverse class of compounds. Subsequent in vitro assessments, including antimicrobial assays, unveiled the pharmacological potential of these derivatives, offering insights into their ability to inhibit pathogenic microorganisms. Molecular docking analysis provided computational insights into the interactions between these compounds and specific biomolecules, shedding light on their potential mechanisms of action. In sum, this comprehensive exploration contributes to the discovery of innovative therapeutic agents, as this bioactive urea and thiourea derivatives hold promise for addressing pressing healthcare challenges.

Combined transcriptome and metabolome analysis revealed the antimicrobial mechanism of Griseorhodin C against Methicillin-resistant Staphylococcus aureus

The global rise of multidrug-resistant pathogens, particularly Methicillin-resistant Staphylococcus aureus (MRSA), has become a critical public health concern, necessitating the urgent discovery of new antimicrobial agents. Griseorhodin C, a hydroxyquinone compound isolated from Streptomyces, has demonstrated significant inhibitory effects against MRSA. In this study, we employed a comprehensive approach combining transcriptome and metabolome analyses to investigate the underlying antimicrobial mechanism of Griseorhodin C. Our findings reveal that Griseorhodin C interferes with multiple bacterial metabolic pathways, including those essential for the biosynthesis and metabolism of amino acids, purine metabolism and energy metabolism, ultimately leading to bacterial growth inhibition and cell death. Notably, Griseorhodin C showed superior inhibitory effects compared to the clinical standard, vancomycin, both in vivo and vitro. These results highlight the potential of Griseorhodin C as a promising candidate for the development of new therapeutic strategies aimed at combating MRSA infections. The study underscores the importance of exploring natural products as sources of novel antibiotics in the ongoing fight against antimicrobial resistance.

“Novel chemo-enzymatic synthesis, structural elucidation and first antiprotozoal activity profiling of the atropoisomeric dimers of trans-8-Hydroxycalamenene”

Leishmaniasis and malaria are two debilitating protozoan diseases affecting millions globally, particularly in tropical and subtropical regions. Current therapeutic options face significant challenges due to emerging drug-resistant strains, necessitating the discovery of novel antiprotozoal agents. This study explores, for the first time, the antiprotozoal potential of calamenenes and their dimers, naturally occurring sesquiterpenes found in essential oils, through a novel chemo-enzymatic synthesis approach. Using the laccase from Trametes versicolor, atropoisomeric dimers of (−)- and (+)-8-trans-hydroxycalamenene were synthesized from commercially available (−)- and (+)-menthol. Structural elucidation was achieved via 2D-NMR spectroscopy, electronic circular dichroism, and DFT calculations. In vitro profiling against Leishmania spp and drug-resistant Plasmodium falciparum revealed that calamenene dimers exhibited significantly higher antiprotozoal activity compared to their monomeric counterparts, highlighting the potential of dimeric terpenoids as promising antiprotozoal agents. This work lays the foundation for developing novel antimalarial drugs based on calamenene scaffolds, encouraging further interactome studies to optimize their pharmacological properties.

An explainable few-shot learning model for the directed evolution of antimicrobial peptides

Due to the persistent threat of antibiotic resistance posed by Gram-negative pathogens, the discovery of new antimicrobial agents is of critical importance. In this study, we employed deep learning-guided directed evolution to explore the chemical space of antimicrobial peptides (AMPs), which present promising alternatives to traditional small-molecule antibiotics. Utilizing a fine-tuned protein language model tailored for small dataset learning, we achieved structural modifications of the lipopolysaccharide-binding domain (LBD) derived from Marsupenaeus japonicus, a prawn species of considerable value in aquaculture and commercial fisheries. The engineered LBDs demonstrated exceptional activity against a range of Gram-negative pathogens. Drawing inspiration from evolutionary principles, we elucidated the bactericidal mechanism through molecular dynamics simulations and mapped the directed evolution pathways using a ladderpath framework. This work highlights the efficacy of explainable few-shot learning in the rational design of AMPs through directed evolution.

Neobacillus driksii sp. nov. isolated from a Mars 2020 spacecraft assembly facility and genomic potential for lasso peptide production in Neobacillus.

The microbial surveillance of the Mars 2020 assembly cleanroom led to the isolation of novel N. driksii with potential applications in cleanroom environments, such as hospitals, pharmaceuticals, semiconductors, and aeronautical industries. N. driksii genomes were found to possess genes responsible for producing lasso peptides, which are crucial for antimicrobial defense, communication, and enzyme inhibition. Isolation of N. driksii from cleanrooms, Agave plants, and dryland wheat soils, suggested niche-specific ecology and resilience under various environmentally challenging conditions. The discovery of potent antimicrobial agents from novel N. driksii underscores the importance of genome mining and the isolation of rare microorganisms. Bioactive gene clusters potentially producing nicotianamine-like siderophores were found in N. driksii genomes. These siderophores can be used for bioremediation to remove heavy metals from contaminated environments, promote plant growth by aiding iron uptake in agriculture, and treat iron overload conditions in medical applications.

Importance of the CuAAC Reaction in the Synthesis of Platinum Complexes with 1,4-Disubstituted-1H-1,2,3-triazoles: A Review of Their Anticancer Activity

Despite multiple advances in treatment and prevention, cancer remains one of the leading causes of death worldwide. Chemotherapy remains the most effective method for cancer treatment. However, commercial chemotherapeutic drugs have limited efficacy, severe side effects, and acquired resistance. Therefore, the scientific community has devoted a great effort to designing new, more effective, and cheaper drugs. In this sense, copper-catalyzed azide-alkyne cycloaddition reactions (CuAAC) provide 1,4-disubstituted 1H-1,2,3-triazoles in high yields without forming by-products. This reaction allows the easy, efficient, functional, ordered, rapid, selective, and specific joining of small molecules, giving rise to more complex molecules. The CuACC reaction simplifies the synthesis processes, accelerating the discovery of new chemotherapeutic agents by allowing the joining of commercial platinum drugs, slightly altering their structure, or creating new molecules with improved properties. This work shows the importance of CuAAC reactions in the search for new metallodrugs with possible anticancer activity.

The pathogenic APP N-terminal Val225Ala mutation alters tau protein liquid-liquid phase separation and exacerbates synaptic damage.

Amyloid precursor protein (APP) is predominantly located in synapses of neurons and its mutations have been well recognized as the most important genetic causal factor for the familial Alzheimer's disease (AD). While most disease-causal mutations of APP occur within the Aβ-coding region or immediately proximal, the pathological impacts of mutations in the N-terminus of APP protein, which remote from the Aβ sequence, on neuron and synapse are still largely unknown. It was recently reported a pathogenic APP N-terminal Val225Ala mutation (APPV225A) with clinically featuring progressive dementia and typical AD pathologies in brain. In our present study, we further found that APPV225A mutation alters the N-terminal structure of APP, which enhances its binding affinity to tau protein and significantly increases APP-mediated endocytosis. Consequently, APPV225A promotes the uptake of extracellular tau into SH-SY5Y cells, further linking the structural change in APP to intracellular tau accumulation. In addition, APPV225A also notably alters the liquid-liquid phase separation (LLPS)of intracellular tau and intensified tauphosphorylation and aggregation in SH-SY5Y cells. Moreover, APPV225A promote AD-like tau pathology and synaptic damages in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells and neurons, as well as in hiPSCs-derived human brain organoids and mouse brain, which can be ameliorated by tau knockdown. Proximity labeling identified several key APPV225A-interacting proteins, including HS3ST3A1, which was shown to directly regulate tau LLPS and phosphorylation. These findings nicely build on our previous work on roles for APP in tau-related pathological phenotypes and further highlight the involvement of N-terminal APP as the key region for both amyloidopathy and tauopathy, two aspects of AD pathogenesis and progression. Our study may also provide a theoretical breakthrough for AD therapy and highlight the important hub roles of APP and making previously neglected N-terminal APP as a potential target for the discovery of novel disease-modifying therapeutic agents against AD, holding significant scientific values and clinical promise.

Integrated workflows using metabolomics, genome mining, and biological evaluation reveal oxepine‑sulfur-containing anti-cryptococcal diketopiperazine produced by the endophyte Penicillium setosum

Cryptococcosis is a fungal infection for which treatment relies on old antifungal agents usually leading to drawbacks such as high toxicity and mainly low efficiency since drug resistance of microorganisms is strongly widespread. The discovery of new antifungal agents is urgent and investigations about underexplored Natural Product (NP) can yield the necessary outcomes to guide the discovery of new prototypes to anti-cryptococcal molecules development. In this scenario, an integrated strategy involving metabolomic data analysis, biological assessement and genome mining of P. setosum CMLD 18, revealed the biosynthesis of bis(methyl-sulfanyl) oxepine-containing diketopiperazine derivative, the bisdethiobis(methylthio)acetylaranotine (1) by the endophyte. The molecule showed a minimum inhibitory concentration (MIC) value of 0.125 mM when tested against C. neoformans. Evidence about the corresponding biosynthetic gene cluster (BGC) responsible for the biosynthesis of (1) in P. setosum were found. Moreover, other putative analogues of (1) were also detected, suggesting this microorganism may represent an important source of likely anti-cryptococcal molecules to be further investigated.

NSC95397 Is a Novel HIV-1 Latency-Reversing Agent.

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the "kick and kill" (also called "shock and kill") approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair-highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.

Introduction to Instruments used in Pharmacology with its Application

Pharmacology is a multidisciplinary field that focuses on the study of drug interactions, mechanisms of action, and therapeutic effects. The advancement of pharmacological research and clinical applications is heavily dependent on various specialized instruments that enable precise measurement, analysis, and monitoring of drug properties and their effects on biological systems. Instruments used in pharmacology range from simple laboratory tools, such as spectrophotometers and chromatographs, to more complex systems like high chromatography (HPLC), mass spectrometry (MS), and in vivo imaging devices. These tools are essential for drug discovery, pharmacokinetic studies, dose assessments, and toxicological evaluations. The development and application of these instruments allow researchers to accurately quantify drug concentrations, monitor physiological changes, and identify potential drug targets, thereby facilitating the discovery of safe and effective pharmaceutical agents. This introduction provides an overview of the fundamental instruments commonly used in pharmacology and highlights their critical roles in modern drug development and research..

Insights into podophyllotoxin lactone features: New cyclolignans as potential dual tubulin-topoisomerase II inhibitors.

Chemomodulation of natural cyclolignans as podophyllotoxin has been a successful approach to obtain semisynthetic bioactive derivates. One example of this approach is the FDA-approved drug etoposide for solid and hematological tumors. It differs from the antimitotic activity of the natural product in its mechanism of action, this drug being a topoisomerase II inhibitor instead of a tubulin antimitotic. Within the molecular requirements for the activity of these compounds, the trans-γ-lactone moiety presented in the parent compound has always been a feature to be explored to chemomodulate its bioactivity. In this study, we have obtained different compounds that comply with the molecular characteristics for antitubulin and antitopoisomerase II activity combined in a single molecule. Furthermore, we explored the influence of the trans-lactone moiety on the final activity, finding that the cis-lactone was also interesting in terms of bioactivity. The best values of cytotoxicity and cell cycle inhibition were obtained for a compound lacking the lactone ring, thus mimicking the podophyllic aldehyde functionalization, a selective antimitotic podophyllotoxin derivate. The analogs with cis-lactone also presented interesting cytotoxic activity. The present study illustrates the potential of the chemomodulation of natural products such as natural cyclolignan podophyllotoxin derivates for the discovery of new antitumor agents.

Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler

Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (AK-4) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies in silico revealed optimal properties of AK-4 for oral administration without potential side effects.

Discovery of anti-tumor agent targeted MetAP-2 using a special turn-on fluorescent probe

Methionine aminopeptidase 2 (MetAP-2) catalyzes the removal of methionine from the amino-terminus of proteins or peptides and is a known target for anti-tumor therapy. In this study, we developed an enzyme-activated fluorescent probe, DDAO-BMT, specifically for the real-time detection of endogenous MetAP-2. This probe enables the determination of extracellular MetAP-2 activity and visual monitoring of intracellular MetAP-2. Additionally, Sappan Lignum was identified as an active herbal medicine against MetAP-2, with brazilin identified as its key active constituent. Brazilin also exhibited a significant anti-tumor effect, including the inhibition on proliferation, migration, and invasion of tumor cells, and the preliminary mechanism of its activity against cancer has been elucidated. The use of this probe facilitates the monitoring of endogenous MetAP-2 in complex biological system, aiding in the discovery of novel active compounds for cancer treatment.

Medicinal plants used in the treatment of urogenital disorders in the Drâa-Tafilalet region of Southeastern Morocco: An ethnobotanical survey

This study presents an ethnobotanical survey of medicinal plants used in the treatment of urogenital disorders in the Drâa-Tafilalet region, located in southeastern Morocco. The survey involved 200 herbalists and medicinal plant vendors across three provinces: Errachidia, Tinghir, and Zagora. Ethnobotanical data were analyzed using metrics such as use value (UV), frequency of citation (FC), relative frequency of citation (RFC), and family importance value (FIV). The study identified 80 species belonging to 44 plant families. The most represented families were Asteraceae (8 species), Lamiaceae (7 species), Apiaceae (7 species), and Fabaceae (6 species). The species most frequently cited treating urogenital disorders included Petroselinum sativum Hoff. (RFC = 0.018), Arenaria rubra L. (RFC = 0.016), Ziziphus lotus (L.) Lank. (RFC = 0.016), Zea mays (RFC = 0.013), Artemisia herba-alba (RFC = 0.013), and Ammi visnaga (RFC = 0.011). Leaves were the most commonly used plant part (35 %). The primary preparation methods of these remedies were decoction (53.75 %) and infusion (30 %), with oral administration being the preferred route (95 %). The findings of this study provide a valuable resource for researchers and practioners of traditional medicine, highlighting the importance of Morocco's medicinal flora. This ethnobotanical knowledge not only supports the conservation of national pharmacopoeia but also offers a promising foundation for the discovery of new therapeutic agents, particularly for the treatment of urogenital disorders. Future research could further investigate the bioactive compounds present in the identified species, potentially leading to innovative treatments for urogenital health issues.

In Situ and Label-Free Quantification of Membrane Protein-Ligand Interactions Using Optical Imaging Techniques: A Review.

Membrane proteins are crucial for various cellular processes and are key targets in pharmacological research. Their interactions with ligands are essential for elucidating cellular mechanisms and advancing drug development. To study these interactions without altering their functional properties in native environments, several advanced optical imaging methods have been developed for in situ and label-free quantification. This review focuses on recent optical imaging techniques such as surface plasmon resonance imaging (SPRi), surface plasmon resonance microscopy (SPRM), edge tracking approaches, and surface light scattering microscopy (SLSM). We explore the operational principles, recent advancements, and the scope of application of these methods. Additionally, we address the current challenges and explore the future potential of these innovative optical imaging strategies in deepening our understanding of biomolecular interactions and facilitating the discovery of new therapeutic agents.

Gas Chromatography-Mass Spectrometry and Fourier Transform Infrared Spectroscopy Analysis of Potential α-Glucosidase Inhibitors from Terminalia catappa Leaf Extracts

Aims: Postprandial hyperglyceamia is often caused by insulin insufficiency or cellular glucose uptake complications, and conventional treatments often yield undesirable side effects. The aim of the current work was to assess the α-glucosidase inhibitory activities of T. catappa leaf extracts and use spectroscopic techniques to partially characterize possible inhibitors. Study Design: Phytochemical screening, enzyme inhibition assay and spectrometric and spectroscopic characterization of bioactive compounds from leaf extract and fractions of T. catappa. Place and Duration of Study: The entire work was carried out at the Department of Applied Chemistry and Biochemistry, University for Development Studies, Ghana within nine months. Methodology: T. catappa leaf extract and fractions were qualitatively screened for phytochemicals and their biological activity assessed in α-glucosidase inhibition assay. The potential enzyme inhibitors were characterized by Gas Chromatography-Mass Spectrometry (GC-MS) and Fourier Transform Infrared (FT-IR) Spectroscopy. Results: Phytochemical screening of the extract and the various solvent fractions revealed the presence of alkaloids, flavonoids, saponins, flavanol glycosides, phenolics, and terpenoids. The α-glucosidase inhibition potential of the crude leaf extract was concentration-dependent with a half-maximal inhibitory concentration (IC50) of 337.5 µg/ml. Solvent fractions from the crude extract demonstrated α-glucosidase inhibitory activity with IC50 values ranging from 170.40 µg/ml for ethyl acetate (EtOAc) fraction to 71.90 µg/ml for n-hexane (n-Hex) fraction. Acarbose, the control drug, demonstrated significant α-glucosidase inhibition activity in a similar pattern with IC50 of 6.16 µg/ml. The enzyme inhibition kinetics parameters, specifically the Michaelis constant (KM) and Maximum reaction velocity (Vmax) values, suggested that the inhibition of α-glucosidase by T. catappa extract followed a competitive mode. GC-MS and FT-IR analysis of the n-Hexane fraction identified the compounds Eugenol, Urs-12-en-24-oic acid, 3-oxo-, methyl ester (+)-, phytol, trans-isoeugenol, α-amyrin, and squalene as the potential antidiabetic agents that might be responsible for reducing postprandial blood glucose levels. Conclusion: These findings show that T. catappa leaf extract contains α-glucosidase inhibitors and therefore serves as a valuable resource in the discovery of natural anti-diabetic agents.