In Silico Design, Synthesis, and Evaluation of Novel Enantiopure Isoxazolidines as Promising Dual Inhibitors of α-Amylase and α-Glucosidase

Molecules, Год журнала: 2024, Номер 29(2), С. 305 - 305

Опубликована: Янв. 6, 2024

Isoxazolidine derivatives were designed, synthesized, and characterized using different spectroscopic techniques elemental analysis then evaluated for their ability to inhibit both α-amylase α-glucosidase enzymes treat diabetes. All synthesized demonstrated a varying range of activity, with IC

Язык: Английский

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LC–MS profiling, in vitro and in silico C-ABL kinase inhibitory approach to identify potential anticancer agents from Dalbergia sissoo leaves

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 2, 2024

Abstract Belonging to the Fabaceae family, Dalbergia sissoo , a versatile plant, has gained prominence for its potent medicinal attributes, especially antipyretic, anti-inflammatory, and cardioprotective properties, as well use of leaf juice in cancer treatment. Despite these recognized applications by natives tribals, comprehensive insight into biological activities chemical composition remains limited. This study aimed explore cytotoxic potential sequentially extracted extracts from using various solvents, aiming unveil array phytochemicals through LC–MS profiling. Among evaluated, extract employing methanol:water extracting media (HN-2) appeared with most remarkable results both phytochemical diversity activity. Furthermore, vitro HN-2's anticancer efficacy were confirmed silico molecular docking dynamics simulation. These analyses demonstrated ability inhibit C-ABL kinase within leukemia K562 cells, directing that leaves serve bioactive agent reservoir. Consequently, this suggests plant is source compounds can be used precursor developing new inhibitors, mainly targeting leukemia.

Язык: Английский

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Repurposing FDA-Approved Drugs for Eumycetoma Treatment: Homology Modeling and Computational Screening of CYP51 Inhibitors

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(1), С. 315 - 315

Опубликована: Янв. 1, 2025

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is neglected tropical disease characterized tumor-like growths that can lead to permanent disability and deformities if untreated. Predominantly affecting regions in Africa, South America, Asia, it imposes significant physical, social, economic burdens. Current treatments, including antifungal drugs like itraconazole, often show variable efficacy, with severe cases necessitating surgical intervention or amputation. Drug discovery for eumycetoma faces challenges due limited understanding of the disease’s molecular mechanisms lack 3D structures key targets such as mycetomatis CYP51, well-known target azoles’ agents. To address these challenges, this study employed computational approaches, homology modeling, virtual screening, free energy calculations, dynamics simulations, repurpose FDA-approved potential treatments targeting CYP51. end, library 2619 was screened, identifying three promising candidates: montelukast, vilanterol, lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions critical residues model stability offering further investigation effective therapeutic options eumycetoma.

Язык: Английский

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Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach

Pharmaceuticals, Год журнала: 2025, Номер 18(1), С. 126 - 126

Опубликована: Янв. 18, 2025

Background/Objectives: Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is promising therapeutic target. α-Mangostin, naturally occurring prenylated xanthone, has been identified an effective KHK-C inhibitor, prompting exploration of its analogs for enhanced efficacy. This study aimed to identify α-Mangostin with improved inhibitory properties against address these disorders. Methods: A library 1383 was compiled from chemical databases the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics simulations, quantum mechani–cal analyses were used screen evaluate compounds. α-Mangostin’s affinity (37.34 kcal/mol) served benchmark. Results: Sixteen demonstrated affinities superior (from −45.51 −61.3 kcal/mol), LY-3522348 (−45.36 reported marine-derived inhibitors −22.74 −51.83 kcal/mol). Hits 7, 8, 9, 13, 15 not only surpassed benchmarks affinity, but also exhibited compared LY-3522348, inhibitors, indicating strong vivo potential. Among these, hit 8 emerged best performer, achieving −61.30 kcal/mol, 100% predicted oral absorption, stability, stable dynamics. Conclusions: Hit most candidate due favorable pharmacokinetics, interactions KHK-C. These findings highlight potential treating fructose-driven warranting further experimental validation.

Язык: Английский

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Alzheimer’s Disease Drug Design by Synthesis, Characterization, Enzyme Inhibition, In Silico, SAR Analysis and MM-GBSA Analysis of Schiff Bases Derivatives

Korean Journal of Chemical Engineering, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

Язык: Английский

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Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 7, 2025

Excessive fructose consumption is a significant driver of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease and steatohepatitis primarily by promoting insulin resistance fat accumulation. Ketohexokinase C (KHK-C), pivotal enzyme in metabolism, catalyzes the phosphorylation to fructose-1-phosphate, initiating cascade downstream processes. In contrast glucose KHK-C lacks negative feedback regulation, allowing continuous fructose, which leads heightened levels glucose, glycogen, triglycerides bloodstream liver. While targeting offers promising therapeutic avenue, no drugs have yet been approved for clinical use. Pfizer's PF-06835919 has progressed phase II trials, demonstrating reduction improved sensitivity, while Eli Lilly's LY-3522348 also shows potential. Nonetheless, there remains critical need development novel inhibitors that offer pharmacokinetics, enhanced efficacy, superior safety profiles. present study, comprehensive computational strategy was employed screen 460,000 compounds from National Cancer Institute library potential inhibitors. Initially, pharmacophore-based virtual screening used identify hits, followed multi-level molecular docking, binding free energy estimation, pharmacokinetic analysis, dynamics (MD) simulations further evaluate compounds. This multi-step approach aimed with strong affinity, favorable profiles, high efficacy as Ten exhibited docking scores ranging -7.79 -9.10 kcal/mol, surpassing those currently undergoing (-7.768 kcal/mol) (-6.54 kcal/mol). Their calculated energies ranged -57.06 -70.69 their superiority over (-56.71 (-45.15 ADMET profiling refined selection five (1, 2, 4-6), identified compound 2 most stable candidate compared PF-06835919. These findings highlight potent inhibitor predicted pharmacokinetics toxicity profiles supporting its treating fructose-driven warranting validation.

Язык: Английский

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Identification of Microbial-Based Natural Products as Potential CYP51 Inhibitors for Eumycetoma Treatment: Insights from Molecular Docking, MM-GBSA Calculations, ADMET Analysis, and Molecular Dynamics Simulations

Pharmaceuticals, Год журнала: 2025, Номер 18(4), С. 598 - 598

Опубликована: Апрель 20, 2025

Background/Objectives: Eumycetoma, caused by Madurella mycetomatis, is a chronic fungal infection with limited treatment options and increasing drug resistance. CYP51, key enzyme in ergosterol biosynthesis, well-established target for azole antifungals. However, existing drugs demonstrate efficacy treating eumycetoma. Microbial-based natural products, their structural diversity bioactivity, offer promising source novel CYP51 inhibitors. This study aimed to identify potential mycetomatis inhibitors from microbial products using molecular docking, MM-GBSA calculations, ADMET analysis, dynamics (MD) simulations. Methods: Virtual screening was conducted on library of microbial-based an in-house homology model itraconazole as the reference drug. The top compounds initial docking were refined through Standard Extra Precision docking. calculations assessed binding affinities, analysis evaluated drug-like properties. Compounds favorable properties underwent MD Results: computational investigations identified 34 better scores affinity than itraconazole. Of these, 9 interacted heme group residues active site CYP51. In silico pharmacokinetic profiling 3 candidates, simulations confirmed Conclusions: highlights microbial-derived particularly monacyclinone G, H, I, candidates inhibition, eumycetoma, requiring further experimental validation.

Язык: Английский

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Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer

SAR and QSAR in environmental research, Год журнала: 2024, Номер 35(10), С. 837 - 875

Опубликована: Окт. 2, 2024

Human aldehyde dehydrogenases (ALDHs) are a group of 19 isoforms often overexpressed in cancer stem cells (CSCs). These enzymes play critical roles CSC protection, maintenance, progression, therapeutic resistance, and poor prognosis. Thus, targeting ALDH offers potential for innovative treatments. Flavonoids, known their ability to affect multiple cancer-related pathways, have shown anticancer activity by downregulating specific isoforms. This study aimed evaluate 830 flavonoids from the PubChem database against five (ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH3A1) using computational methods identify potent inhibitors. Extra precision (XP) Glide docking MM-GBSA free binding energy calculations identified several with high affinities. MD simulation highlighted 1, 2, 18, 27, 42 as inhibitors each isoform, respectively. Flavonoid 10 showed affinities ALDH3A1, emerging multi-ALDH inhibitor. ADMET property evaluation indicated that promising hits acceptable drug-like profiles, but further optimization is needed enhance efficacy reduce toxicity, making them more effective future treatment.

Язык: Английский

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Unveiling the Anticancer Potential: Computational Exploration of Nitrogenated Derivatives of (+)-Pancratistatin as Topoisomerase I Inhibitors

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10779 - 10779

Опубликована: Окт. 7, 2024

Cancer poses a substantial global health challenge, driving the need for innovative therapeutic solutions that offer improved effectiveness and fewer side effects. Topoisomerase I (Topo I) has emerged as validated molecular target in pursuit of developing anticancer drugs due to its critical role DNA replication transcription. (+)-Pancratistatin (PST), naturally occurring compound found various Amaryllidaceae plants, exhibits promising properties by inhibiting Topo activity. However, clinical utility is hindered issues related limited chemical availability aqueous solubility. To address these challenges, modelling techniques, including virtual screening, docking, mechanics with generalised born surface area solvation (MM-GBSA) calculations, dynamics simulations were utilised evaluate binding interactions energetics PST analogues I, comparing them well-known inhibitor, Camptothecin. Among compounds screened this study, nitrogenated most encouraging drug candidates, exhibiting affinities, favourable active site stability protein-ligand complex. Structural analysis pinpointed key determinants responsible heightened potency analogues, shedding light on essential structural modifications increased Moreover, silico absorption, distribution, metabolism, excretion, toxicity (ADMET) predictions highlighted drug-like reduced profiles prominent further supporting their potential effective agents. In summary, screening study underscores significance nitrogenation augmenting efficacy targeting I. The identified lead exhibit significant subsequent experimental validation optimisation, thus facilitating development novel efficacious therapeutics enhanced pharmacological profiles.

Язык: Английский

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α-Amylase and mycobacterium-TB H37Rv antagonistic efficacy of novel pyrazole-coumarin hybrids: an in vitro and in silico investigation

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 42(23), С. 12788 - 12805

Опубликована: Окт. 30, 2023

The present investigation of minutiae to acquire structural information the novel pyrazole-coumarin hybrids (PC1-PC10) synthesized using ultrasound methods and characterized different spectroscopic techniques: mass, 1H-NMR, 13 C-NMR IR spectroscopy, theoretically explored DFT approach with a B3LYP/6–311G (d, p) basis set, there in vitro, antagonistic efficacy against α-amylase mycobacterium-TB H37Rv are described this article. Pyrazole-coumarin showed inhibition ranging from IC50 (0.32–0.58 mM) when compared acarbose (IC50 = 0.34 mM). Similarly, Mycobacterium-TB strain screening MIC values 62.5 1000 µg/mL rifampicin isoniazid 0.25 0.20 µg/mL, respectively. Molecular docking MD simulation studies were performed determine active sites rationalize activities compounds. To investigate binding conformation dynamics responsible for their activity, three most compounds (PC1, PC3 PC6) docked into porcine pancreatic site (PDB ID:1OSE), ID: 4TZK). interactions between PC1, PC3, PC6 like those inhibiting by acarbose. Also, residues standard rifampicin.

Язык: Английский

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