Sá Magalhães Serafim M, Kronenberger T, Francisco KR
… +17 more, de Sousa Reis EV, Gonçalves de Oliveira E, Marcelino E Oliveira FK, Serraglio Fortes I, Maciel Fernandes TH, Barbosa da Silva E, Fajtova P, Skinner DE, Syed RO, Lage de Siqueira-Neto J, Poso A, Fernandes Mota BE, Alves Coelho-Dos-Reis JG, Santos Abrahão J, Gonçalves Maltarollo V, O'Donoghue AJ, Caffrey CR
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41246830
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The constant emergence of SARS-CoV-2 resistance drives the search for new antivirals. We screened the SARS-CoV-2 cysteine proteases, the main protease (M) and papain-like protease (PL), with 141 peptidyl and peptidomimet...The constant emergence of SARS-CoV-2 resistance drives the search for new antivirals. We screened the SARS-CoV-2 cysteine proteases, the main protease (M) and papain-like protease (PL), with 141 peptidyl and peptidomimetic inhibitors designed to target a trypanosome cysteine protease. Five compounds (-) inhibited M (IC of 0.1601-16.42 µM), whereas none inhibited PL. Compounds - inhibited human cathepsin L (hCatL; 0.184-10.74 µM), which is important for viral entry into human cells. Compounds and , and its synthesised (R,S) enantiomer, , which share a benzyl carbamate moiety, inhibited the M of SARS-CoV/MERS-CoV (0.0732-0.8295 µM). The three compounds were biochemically characterised as covalent reversible inhibitors. Compounds and , which contain vinyl ketone warheads, were specific for M, and this behaviour was supported by covalent and noncovalent computational simulations. This study highlights the importance of revisiting legacy assets to identify starting points for new antiviral drugs.
Guo Y, Long H, Zhang H
… +6 more, Wang D, Wu H, Chen X, Mao L, Gao E, Wang T
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41236513
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Targeted cancer drug therapy has emerged as a critical treatment modality for advanced hepatocellular carcinoma (HCC). The discovery and development of novel anti-HCC drug therapeutics with improved pharmacological prope...Targeted cancer drug therapy has emerged as a critical treatment modality for advanced hepatocellular carcinoma (HCC). The discovery and development of novel anti-HCC drug therapeutics with improved pharmacological properties remains an urgent priority in oncology drug discovery. In this study, we designed and synthesised a new series of 1,2,3-triazole-cored structures incorporating aryl urea. Fifteen analogs were prepared nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. These synthesised compounds were evaluated for their potential antitumor activities. Notably, compounds and exhibited the lowest IC values (10.80 ± 0.14 and 11.62 ± 3.72 μM) against HuH-7 cells. Further investigations suggested compound and induced cell apoptosis, stimulated DNA damage, and autophagy against HuH-7 cells. Acute toxicity measurement also demonstrated the safety of the compounds. These findings suggested the triazole-cored analogs and are suggested to be promising candidates for the treatment of HCC and their potential for further pharmaceutical development.
Feng A, Zeng Q, Wang J
… +6 more, Li H, Fang X, Geng Y, Pan W, Li G, Dong J
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41224696
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Spinal cord injuries (SCIs) cause irreversible damage and lasting neurological impairments. Current treatments are limited to surgical and pharmaceutical interventions, underscoring the need for novel agents. In this stu...Spinal cord injuries (SCIs) cause irreversible damage and lasting neurological impairments. Current treatments are limited to surgical and pharmaceutical interventions, underscoring the need for novel agents. In this study, 27 novel pyrazole derivatives were designed, synthesised. The anti-inflammatory and antioxidant activities of the compounds were systematically evaluated utilising lipopolysaccharide-stimulated BV2 microglial cells. Anti-inflammatory activity was assessed by quantifying the mRNA expression levels of key pro-inflammatory cytokines [tumour necrosis factor-α, interleukin-1β, and interleukin-6 (IL-6)] via quantitative reverse transcription polymerase chain reaction. Among the synthesised derivatives, compound demonstrated the most potent anti-inflammatory effect, exhibiting an IC value of 9.562 μM for the suppression of IL-6 expression and no significant cytotoxicity was observed. Notable, compound exhibited better inhibitory potency against IL-6 expression compared to the anti-inflammatory drugs dexamethasone and Celecoxib. These findings strongly support the potential of compound as a promising therapeutic candidate for mitigating secondary inflammation in SCI.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41224694
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A series of 1, 3-dioxo-phenylisoindoline-5-carboxamide derivatives were designed, synthesised and evaluated as potent human monoamine oxidase B (MAO-B) inhibitors with neuroprotective properties. The structure-activity r...A series of 1, 3-dioxo-phenylisoindoline-5-carboxamide derivatives were designed, synthesised and evaluated as potent human monoamine oxidase B (MAO-B) inhibitors with neuroprotective properties. The structure-activity relationship (SAR) was summarised. The most potent compound identified in the study, compound , exhibited significant MAO-B inhibition (IC = 0.011 μM) and remarkable selectivity (selectivity index > 3636) over MAO-A. Kinetic analysis confirmed that compound acted as a mixed-type, reversible MAO-B inhibitor. Molecular docking studies provided insights into the interactions between the inhibitor and the enzyme. In cellular assays, compound significantly reduced the production of nitric oxide (NO) and tumour necrosis factor-alpha (TNF-α) in lipopolysaccharide (LPS)-stimulated BV-2 cells. Additionally, compound also exhibited notable antioxidant activity. These findings suggested that compound could be developed as a promising lead for further investigation.
Lamanna G, Augello G, Ronga L
… +6 more, Tesauro D, Silvestri I, Azzolina A, Cervello M, Mangiatordi GF, Saviano M
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41211658
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Thioredoxin reductase 1 (TrxR1), a selenoprotein enzyme crucial for redox homeostasis in mammals, has emerged as a promising target for anticancer therapy. In this study, we present a non-covalent TrxR1 inhibitor, identi...Thioredoxin reductase 1 (TrxR1), a selenoprotein enzyme crucial for redox homeostasis in mammals, has emerged as a promising target for anticancer therapy. In this study, we present a non-covalent TrxR1 inhibitor, identified through an integrated experimental and computational approach. After identifying a plausible druggable cavity, a molecular docking-based virtual screening of over 90,000 lead-like compounds was performed. The selected compounds were evaluated for their impact on TrxR1 activity, leading to the identification of the most promising candidate, . The identified compound, already proven to be free from potential ADMET concerns, inhibits TrxR1 in a dose-dependent manner, with an IC value in the micromolar range. C55's activity was confirmed across multiple cancer cell lines, including HepG2, Huh7, MCF-7, and MDA-MB-231 cells. As a metal-free organic molecule capable of non-covalently inhibiting TrxR1, C55 represents a significant breakthrough, offering a solid foundation for hit-to-lead optimisation and the development of new anticancer drug candidates.
Meza-Ireta SA, Romero-Hernández LL, Begines P
… +14 more, Giouvannuzi S, Puerta A, González-Bakker A, Romero-Franco A, Huertas P, Nocentini A, Vega-Báez JL, Montiel-Smith S, Fernández-Bolaños JG, Castellano-Pozo M, Padrón JM, Supuran CT, Merino-Montiel P, López Ó
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41211653
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We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural...We synthesised coumarin-based derivatives bearing thio- and selenocyanates to selectively inhibit tumour-associated carbonic anhydrases (CAs) IX and XII and to exert antiproliferative effects on tumour cells. Structural variations included chalcogen atom type (S, Se), substitutions at C-3/C-4, and tether length at C-7 of the coumarin core. Thiocyanates and showed potent CA IX/XII inhibition ( = 17.9-27.4 nM) with >5000-fold selectivity over off-target isoforms (CAs I and II). Selenocyanate exhibited strong antiproliferative activity (GI = 0.78-2.6 µM) across six human solid tumour cell lines. Mechanistic studies revealed a cytostatic effect cell cycle arrest and reduced mitotic progression. assays in confirmed selective cytostatic action of selenocyanate , reducing tumorous germline size without affecting healthy tissues at therapeutic doses.
Gao S, Shi X, Yang S
… +3 more, Wang Y, Wang Q, Yang M
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41198593
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Inhibition of the Keap1-Nrf2 protein-protein interaction with cyclic peptides represents an attractive strategy to treat inflammation. However, the cyclic peptides for this inhibition are constrained by their low affinit...Inhibition of the Keap1-Nrf2 protein-protein interaction with cyclic peptides represents an attractive strategy to treat inflammation. However, the cyclic peptides for this inhibition are constrained by their low affinity. In this study, the peptides 1-6 were computationally screened using Keap1-pharmacophore modelling, toxicity screening, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that peptide-4 exhibited potent binding affinity for Keap1 ( = 7.1 ± 0.2 nM). MD simulations further demonstrated that peptide-4 stably bound to Keap1. Additionally, MTT assays confirmed that peptides 1-6 induced negligible cytotoxicity in RAW264.7 macrophages. anti-inflammatory experiments indicated that peptide-4 significantly inhibited the mRNA and protein expression of IL-6 and TNFα in LPS-induced RAW264.7 cells. More importantly, experiments in Keap1-knockout RAW264.7 macrophages confirmed that the anti-inflammatory activity of peptide-4 was highly Keap1-dependent. In conclusion, the data demonstrated that the peptide-4 may be a promising candidate cyclic peptide to treat inflammatory disease.
Li XD, Ma NS, He CY
… +4 more, Zou LW, Zhang J, Ni ZH, Ling Y
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41186213
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The environmental pollutant benzo[a]pyrene (BaP) can induce cytochrome P450 family 1 subfamily A (CYP1A) or generate metabolic products that disrupt the balance of oxidative stress, triggering inflammatory responses in t...The environmental pollutant benzo[a]pyrene (BaP) can induce cytochrome P450 family 1 subfamily A (CYP1A) or generate metabolic products that disrupt the balance of oxidative stress, triggering inflammatory responses in the lungs and leading to tissue damage. Flavonoids, known for their natural anti-inflammatory and antioxidant properties, are potential targets for intervention. This study used phenacetin, a specific substrate probe for CYP1A, to evaluate the inhibitory effects of 40 flavonoids on CYP1A. Structure-activity relationship analysis revealed that introducing hydroxyl groups at positions 3- and 6-enhances CYP1A inhibition. Notably, 3,6-dihydroxyflavone (DHF) emerged as a significant inhibitor of CYP1A. In vitro experiments confirmed that DHF effectively inhibits BaP-induced cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in airway epithelial cells and shows dose-dependent inhibition of intracellular and mitochondrial reactive oxygen species (ROS) production. In summary, DHF is a promising CYP1A inhibitor and a potential anti-inflammatory candidate for preventing and treating CYP1A-mediated lung diseases.
Valadbeigi S, Saghiri R, Kianmehr Z
… +2 more, Mirzazadeh R, Khatami S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41186211
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ABSTRRACTAlpha-glucosidase inhibitors have been considered as the most effective agents in preventing hyperglycaemia and alternative targets for the treatment of Diabetes mellitus (DM). This study aimed to synthesise nov...ABSTRRACTAlpha-glucosidase inhibitors have been considered as the most effective agents in preventing hyperglycaemia and alternative targets for the treatment of Diabetes mellitus (DM). This study aimed to synthesise novel phenyl carbamoyl methoxy thiosemicarbazone derivatives and evaluate their potential as α-glucosidase inhibitors through biochemical assays, cytotoxicity screening, molecular docking, and molecular dynamics simulations. The tested derivatives exhibited a range of inhibitory potential, from moderate to strong as compared to acarbose. Derivative 7e revealed the least IC50 value among the tested compounds. 7e in the kinetic assay acted as a competitive inhibitor of the α-glucosidase. The cytotoxic effect 7e was assessed against the A549 and MDA-MB-453 cell lines. MD simulation revealed that could affect the stability, flexibility, thermodynamics, and structure of α-glucosidase enzymes such as acarbose. Compound 7e demonstrates strong α-glucosidase inhibitory activity with low cytotoxicity in both cell lines, underscoring its potential as a lead candidate for antidiabetic drug development.
Codony S, Jora B, Santos-Caballero M
… +23 more, Qiu Q, Calvó-Tusell C, Escriche C, Turcu AL, Prischi F, Bartra C, Val C, Morisseau C, Pérez B, Bertran-Mostazo A, Osuna S, Corpas R, Griñán-Ferré C, Galdeano C, Loza MI, Pallàs M, Sanfeliu C, Hammock BD, Brea J, Feixas F, Conte MR, Cobos EJ, Vázquez S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41128518
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The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor w...The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor with high potency and good Drug Metabolism and Pharmacokinetics (DMPK) properties. Molecular dynamics and X-ray crystallography helped reveal the binding of these inhibitors to sEH. The selected compound showed a robust analgesic effect in a dose-dependent manner in a murine model of chemotherapy-induced neuropathic pain (CINP). Moreover, the compound also prevented the development of paclitaxel-induced neuropathic pain. Overall, these results suggest that peripheral inhibition of sEH might constitute a novel therapy to prevent and treat CINP.
Li M, You X, Yuan T
… +9 more, He J, Xu Z, Liang S, Mao L, Jin A, Zhou X, Yi B, Li J, Tu Q
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41117311
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HCC is a highly lethal cancer characterised by significant sorafenib resistance, leading to poor patient outcomes. Recent studies have suggested that MED8 plays a role in enhancing tumour resistance to drugs, but its rol...HCC is a highly lethal cancer characterised by significant sorafenib resistance, leading to poor patient outcomes. Recent studies have suggested that MED8 plays a role in enhancing tumour resistance to drugs, but its role in drug resistance in HCC has not yet been reported. This study found significantly higher MED8 expression in HCC tissues compared to adjacent noncancerous tissues. Increased MED8 expression in HCC correlates with poorer overall survival. Functional assays demonstrated that reduced MED8 expression inhibited HCC cell proliferation and epithelial-mesenchymal transition, promoted apoptosis, and increased sensitivity to sorafenib. Overexpression of MED8 elevated TRIP4 protein levels. TRIP4 overexpression negated the effects of MED8 knockdown, whereas TRIP4 suppression inhibited MED8-driven EMT. Mechanistically, MED8 interacts with TRIP4, reducing its ubiquitination and stabilising TRIP4 protein levels. Our findings indicate that the MED8-TRIP4 axis plays a role in sorafenib resistance in HCC and could serve as a therapeutic target for HCC treatment.
Kulkarni NV, S A A, S A I
… +6 more, Senthurpandi D, Bojilov DG, Manolov SP, Ivanov II, Al-Otaibi JS, Mary YS
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41071067
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Two edaravone derivatives were synthesised and characterised by using several spectral and analytical techniques. The antioxidant activities of these organic compounds were analysed by using HPSA, DPPH and ABTS·+ assays....Two edaravone derivatives were synthesised and characterised by using several spectral and analytical techniques. The antioxidant activities of these organic compounds were analysed by using HPSA, DPPH and ABTS·+ assays. Anti-inflammatory property of the synthesised derivatives was analysed by evaluating albumin denaturation inhibition abilities. Optical energy band gaps were evaluated using the Tauc plots. Computational method was used to analyse the frontier molecular orbitals of the compounds and MEP surface analysis was used to identify the nucleophilic and electrophilic attacking sites. Owing to the higher antioxidant potential the interaction of the compound with the protein Tyrosinase (isolated from the bacterium, ) was investigated using detailed molecular docking and simulation methods. Compound exhibited higher free radical scavenging activity, good anti-inflammatory property and found to effectively bind to the Tyrosinase protein. These derivatives have potential application in the production of improved antioxidant and anti-inflammatory agents as well as cosmeceuticals.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41065365
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Protein kinase CK2 is a promising therapeutic target, and this study explores 54 aurone derivatives as potential CK2 inhibitors. Activity was evaluated using luminescent and capillary electrophoresis assays, identifying...Protein kinase CK2 is a promising therapeutic target, and this study explores 54 aurone derivatives as potential CK2 inhibitors. Activity was evaluated using luminescent and capillary electrophoresis assays, identifying 17 compounds with submicromolar activity. The most potent inhibitors shared key structural features: a benzo group on the A-ring, a hydrogen bond acceptor at the R4' position, and an additional substituent at the R3' position of the B-ring. Molecular docking revealed similar binding modes among active compounds, with interactions involving Leu45, Val53, Val66, Met163, Phe113, Lys68, and Ile174. Notably, BFO25 showed the highest activity (IC = 3 nM at 100 μM ATP). These findings highlight aurones as promising CK2 inhibitors and emphasise the significance of specific structural features.
Peng J, Zheng K, Ren L
… +3 more, Cheng J, Feng X, Zhang R
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41065364
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Acute lymphoblastic leukaemia (ALL) is a highly aggressive hematological malignancy that necessitates safer, more effective therapies. This study applied a multi-parametric computational approach to identify KRAS (G12C)...Acute lymphoblastic leukaemia (ALL) is a highly aggressive hematological malignancy that necessitates safer, more effective therapies. This study applied a multi-parametric computational approach to identify KRAS (G12C) inhibitors from African natural product databases. Six lead compounds (NA/EA-1 to NA/EA-6) were identified via virtual screening, molecular docking, and induced-fit docking, all showing stronger binding affinities (-14.50 to -10.53 kcal/mol) than the reference inhibitor Sotorasib (-8.34 kcal/mol). These candidates exhibited favorable pharmacokinetic and physicochemical properties, minimal Lipinski's rule violations, and non-toxic ADMET profiles. Four top hits were subjected to 200 ns molecular dynamics simulations, with NA/EA-3 demonstrating the greatest stability, lowest RMSD, and strongest hydrogen bonding. MM/GBSA analysis confirmed NA/EA-3 as the most promising compound (ΔG -54.42 kcal/mol), outperforming Sotorasib (-32.88 kcal/mol). These findings highlight NA/EA-3 as a potential KRAS(G12C) inhibitor for ALL therapy, warranting experimental validation.
Moloi L, Samson S, Tshiyoyo K
… +4 more, Maluleke K, Oberholzer M, Baloyi I, Malgas S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41031657
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The food industry relies on citrus fruits for juice, canned fruit, and jam, creating significant waste from peels, seeds, and pomace. This waste contains valuable phytochemicals like carotenoids, essential oils, (poly)ph...The food industry relies on citrus fruits for juice, canned fruit, and jam, creating significant waste from peels, seeds, and pomace. This waste contains valuable phytochemicals like carotenoids, essential oils, (poly)phenols, pectin, and vitamins, which can be used as nutraceuticals or key ingredients in functional foods for managing diabetes and obesity. Repurposing citrus peel waste offers an excellent opportunity to advance biorefineries and the bioeconomy. Compounds derived from citrus have attracted attention for their potential therapeutic effects on diabetes and obesity, and their effectiveness depends on various mechanisms. This review summarises citrus-derived phytochemicals that inhibit α-glucosidase and pancreatic lipase , highlighting their potential as anti-diabetic and anti-obesity compounds. We also discuss progress in using molecular docking screening against key drug targets linked to type II diabetes and obesity. This review explores novel citrus phytochemicals for the development of nutraceuticals and functional food ingredients with enhanced health benefits.
Moosavinejad N, Nasiri Sarvi Z, Gholamhosseinian H
… +2 more, Iranshahi M, Rassouli FB
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41026084
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This study evaluated Farnesiferol C (FC), a natural coumarin, as a potential topoisomerase IIα (TOP2A) inhibitor to enhance chemotherapy and ionising radiation (IR) efficacy in melanoma cells. Key targets were identified...This study evaluated Farnesiferol C (FC), a natural coumarin, as a potential topoisomerase IIα (TOP2A) inhibitor to enhance chemotherapy and ionising radiation (IR) efficacy in melanoma cells. Key targets were identified, followed by enrichment and gene expression analyses, and molecular docking and dynamics simulations. Upon extraction of FC from , cell treatment with FC, alone or combined with IR or temozolomide (TMZ), was performed, and viability and apoptosis were assessed. TOP2A emerged as a hub target, showing elevated expression in melanoma and a negative correlation with patient survival. Simulations demonstrated stable binding of FC at the ATP-binding site of TOP2A. Experimental data revealed selective cytotoxicity of FC on A375 melanoma cells (IC: 76.9 µM, SI: 4.97), sparing normal fibroblasts. Combination treatments with IR or TMZ further increased cytotoxicity and apoptosis. These findings suggest FC as a promising TOP2A inhibitor that potentiates the DNA damage effects of chemoradiotherapy in melanoma.
Zhou H, Guan L, Lin G
… +5 more, Yang X, Zhang X, Si Y, Zhang Y, Chen J
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 41026045
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Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) tar...Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1-5 had strong binding affinity for PLK1, especially PL-1 ( = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.
Sun Z, Wang J, Li F
… +5 more, Huang L, Zheng S, Guan Q, Wang Z, Zhang W
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40985578
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Based on conformational preference of SMART analogues and conformational constraint strategy, two series of new tubulin polymerisation inhibitors (- and -/-) were designed hydrogen bonding, steric effect (for -) and rin...Based on conformational preference of SMART analogues and conformational constraint strategy, two series of new tubulin polymerisation inhibitors (- and -/-) were designed hydrogen bonding, steric effect (for -) and ring-closing approach by fused five- and seven-membered ring (for -/-) which was first adopted in the design of new SMART analogues. Among these compounds, and showed potent activities with IC values of 15 nM and 6 nM against PC-3 cell line. Mechanism studies indicated that and could inhibit tubulin polymerisation, arrest cell cycle at G/M phase, induce cell apoptosis, and inhibit cell migration and colony formation. Molecular docking suggested that compounds and could bind into the colchicine binding site at the pose similar to DAMA-colchicine. Western blot assays revealed that and regulated the expression of cell cycle and apoptosis-related proteins. Prediction of physicochemical properties indicated good drug-likeness of and .
Li CH, Tung MC, Tsai CK
… +2 more, Ju TC, Tseng TS
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40960081
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Inflammation plays a central role in various diseases, necessitating effective anti-inflammatory agents. Prostaglandin D2 (PGD2), a key mediator synthesised by haematopoietic prostaglandin D synthase (H-PGDS), is linked...Inflammation plays a central role in various diseases, necessitating effective anti-inflammatory agents. Prostaglandin D2 (PGD2), a key mediator synthesised by haematopoietic prostaglandin D synthase (H-PGDS), is linked to allergic and inflammatory conditions. This study employed pharmacophore-based screening to identify inhibitors targeting H-PGDS. The model identified (IC50 = 88.9 ± 1.1 µM) as a potential inhibitor. Further analysis revealed that its analog (dihydroberberine) demonstrated the most potent inhibitory activity (IC = 3.7 ± 1.1 µM) and binding affinity (KD = 3.2 ± 0.74 µM). Molecular dynamics simulations revealed stabilising interactions, including π-π stacking, hydrogen bonding, and hydrophobic contacts, in the H-PGDS- complex. Functional assays confirmed that significantly reduced PGD2 production in KU812 cells. These findings highlight as a promising candidate for the treatment of inflammatory and allergic diseases, including Duchenne muscular dystrophy, demonstrating both potent inhibitory activity and strong binding characteristics.
Sah VK, Singh AK, Kumar A
… +7 more, Prajapati V, Kalsi AS, Khalilullah H, Jaremko M, Emwas AH, Verma A, Kumar P
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40928301
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The mitogen-activated protein kinase (MAPK) pathway-also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the earl...The mitogen-activated protein kinase (MAPK) pathway-also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the early 1980s, the pathway's extracellular signal-regulated kinase (ERK) subfamily was identified in the 1990s. The ERK family includes several isoforms-ERK1, ERK2, ERK3, ERK5, and ERK6-with ERK1 (MAPK3) and ERK2 (MAPK1) being the most well-characterised and playing central roles in MAPK signalling. Deregulation of ERK signalling (commonly referred to as the ERK pathway or ERKp) has been implicated in approximately 40% of human cancers. This review focuses on the structural insights of ERK1/2 and their critical role in the MAPK signalling cascade. Despite their clinical significance, no ERK inhibitors have yet been approved by the FDA. Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.