Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP+ cofactor, while the C17α-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

• Keywords
• AKR1C3, CYP17, molecular docking, prostate cancer, protein X-ray crystallography,
• MeSH
• Androstanes * chemistry   pharmacology   chemical synthesis   MeSH
• Enzyme Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Molecular Structure MeSH
• Aldo-Keto Reductase Family 1 Member C3 * antagonists & inhibitors   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• AKR1C3 protein, human MeSH Browser
• Androstanes * MeSH
• Enzyme Inhibitors * MeSH
• Aldo-Keto Reductase Family 1 Member C3 * MeSH

OBJECTIVE: This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7'-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold. METHODS: The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells. RESULTS: In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with KI values ranging from 0.75 to 10.5 μM, while hCA I, II, IV isoforms were not significantly inhibited (KIs > 100 μM). Compound 3d emerged as the most potent and selective inhibitor, with KIs of 0.92 and 0.75 μM for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin. CONCLUSION: In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices > 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

• Keywords
• 2, 4]triazolo[1, 5-a]pyrimidine, Carbonic anhydrase inhibitors, [1, antiproliferative activity, coumarin, isoform selectivity, structure– activity relationship.,
• MeSH
• Antigens, Neoplasm metabolism   MeSH
• Apoptosis drug effects   MeSH
• Carbonic Anhydrase Inhibitors * pharmacology   chemical synthesis   chemistry   MeSH
• Carbonic Anhydrase IX * antagonists & inhibitors   metabolism   MeSH
• Carbonic Anhydrases * metabolism   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Pyrimidines * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Design * MeSH
• Drug Screening Assays, Antitumor MeSH
• Molecular Docking Simulation MeSH
• Triazoles * chemistry   pharmacology   chemical synthesis   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Neoplasm MeSH
• CA9 protein, human MeSH Browser
• carbonic anhydrase XII MeSH Browser
• Carbonic Anhydrase Inhibitors * MeSH
• Carbonic Anhydrase IX * MeSH
• Carbonic Anhydrases * MeSH
• Antineoplastic Agents * MeSH
• Pyrimidines * MeSH
• Triazoles * MeSH

Given the limited benefits of anticholinergic drugs and the repeated clinical failures of anti-amyloid therapies, the therapeutic focus in Alzheimer's disease (AD) is gradually shifting toward addressing both disease symptoms and its major underlying cause - neuroinflammation. We have developed novel multi-target directed ligands that inhibit butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) to simultaneously target cholinergic deficits and neuroinflammation in AD. Following in silico design, we converted known allosteric pyrazolyl urea p38α MAPK ligands into N,N-disubstituted carbamates that pseudo-irreversibly inhibit hBChE while retaining p38α MAPK inhibitory activity. The lead compound 13a has favourable central nervous system (CNS) drug-like properties in vitro and shows procognitive effects in an in vivo scopolamine-induced amnesia model. Our series demonstrates that targeted structural modifications of selective kinase inhibitors, based on a comprehensive knowledge of cholinesterase structure and function, enable expansion of the effect to the CNS. This approach offers critical insights to pave the way for the development of novel dual-target agents that modulate both cholinergic and neuroinflammatory pathways in neurodegenerative diseases.

• Keywords
• Butyrylcholinesterase, Carbamate, Dual inhibitors, p38α mitogen-activated protein kinase, pseudo-irreversible inhibition,
• Publication type
• Journal Article MeSH

The therapeutic efficacy of antitumor nanomedicines is influenced by numerous factors, with the most critical being the selection of an appropriate biomaterial and the use of suitable stimulus-responsive linkers. The chosen biomaterial must be biocompatible and capable of binding the drug via a linker that facilitates selective release and activation of the therapeutic effect, specifically within tumor tissue. In this study, we designed, synthesized, and compared the physicochemical and biological properties of various polymer nanomedicines, each bearing pirarubicin conjugated to water-soluble and biocompatible methacrylamide-based copolymers through pH-sensitive hydrazone bonds. Our findings indicate that the hydrophobicity and length of the linker near the hydrazone bond are crucial factors influencing the treatment efficacy of the nanomedicines. Conjugates with aminohexanoyl linkers exhibited superior drug release and enhanced antitumor activity compared with those with shorter linkers. Overall, our study highlights that the rate of drug release, governed by the linker structure, plays a pivotal role in therapeutic efficacy, while the hydrophilicity of the polymer backbone has a lesser impact.

• Publication type
• Journal Article MeSH

The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.

• MeSH
• Alzheimer Disease drug therapy   MeSH
• Butyrylcholinesterase * chemistry   metabolism   MeSH
• Cholinesterase Inhibitors * pharmacology   chemistry   therapeutic use   MeSH
• Protein Kinase Inhibitors * pharmacology   chemistry   therapeutic use   MeSH
• Cognitive Dysfunction * drug therapy   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Lipopolysaccharides MeSH
• Mitogen-Activated Protein Kinase 14 * antagonists & inhibitors   metabolism   MeSH
• Models, Molecular MeSH
• Mice MeSH
• Neuroinflammatory Diseases * drug therapy   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Butyrylcholinesterase * MeSH
• Cholinesterase Inhibitors * MeSH
• Protein Kinase Inhibitors * MeSH
• Lipopolysaccharides MeSH
• Mitogen-Activated Protein Kinase 14 * MeSH

The use of artificial intelligence (AI) is increasingly integral to the drug-discovery process, and among AI-driven methodologies, deep generative models stand out as one of the most promising approaches for hit identification and optimization. Here, we report a retrospective benchmarking analysis of a series of tubulin inhibitors, 3-aroyl-1,4-diarylpyrroles (ARDAP), using the deep-generative algorithm Molecule Optimization by Reinforcement Learning and Docking (MORLD) in combination with five docking software (QuickVina 2, AutoDock-GPU, PLANTS, GOLD, and Glide). Our results indicate that the performance of the MORLD/docking workflow is highly dependent on the availability of initial structural information; only the incorporation of a core constraint in Glide yields satisfactory predictions. To address this limitation, we developed a docking-free variant of MORLD that exploits receptor-derived shape similarity and pharmacophore alignment. Kernel-density estimation, convergence analysis, and SMARTS-based success-rate metrics confirmed that this Shape-Pharmacophore implementation autonomously generates chemically valid, SAR-consistent analogues of the reference compounds. Collectively, this work demonstrates a practical, structure-only driven paradigm for reinforcement-learning-based compound optimization, thereby extending the reach of AI-enabled drug design beyond traditional docking workflows.

• MeSH
• Algorithms MeSH
• Benchmarking MeSH
• Pharmacophore MeSH
• Tubulin Modulators * chemistry   pharmacology   metabolism   MeSH
• Drug Discovery MeSH
• Pyrroles * chemistry   pharmacology   metabolism   MeSH
• Retrospective Studies MeSH
• Molecular Docking Simulation * MeSH
• Tubulin metabolism   chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Tubulin Modulators * MeSH
• Pyrroles * MeSH
• Tubulin MeSH

Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine-based C1'-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1' atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest Ki values for two of these inhibitors are 0.7 µM for the human enzyme and 0.4 µM for the parasite enzyme. The Ki values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1' atom. A phosphonodiamidate prodrug of one of the compounds has an IC50 of 4.3 µM against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.

• Keywords
• Plasmodium falciparum, acyclic nucleoside phosphonates, docking, hypoxanthine‐guanine‐(xanthine) phosphoribosyltransferase, inhibitors, malaria,
• Publication type
• Journal Article MeSH

Cancer remains a leading cause of mortality worldwide, with conventional therapies showing limited efficacy and high toxicity. The increasing incidence and therapeutic resistance necessitate alternative strategies. In this regard, phytochemicals have emerged as potential sources of developing safer and novel anti-cancer agents. This study employs a structure-based drug design approach, integrating molecular docking, molecular dynamics (MD) simulations, and in silico profiling, to investigate the anti-cancer potential of metabolites from Curcuma caesia rhizomes. The research targets key cancer-associated proteins, Matrix Metalloproteinase-9 (MMP9) and Glucose-Regulated Protein 78 (GRP78), identified through expression analysis, functional network mapping, and pathway enrichment as critical mediators of cancer progression and metastasis. A comprehensive molecular docking analysis of 101 bioactive compounds from C. caesia rhizomes identified curcumin and bis-demethoxycurcumin as promising candidates, demonstrating high binding affinities and stable interactions with MMP9 and GRP78. MD simulations further validated the stability and robustness of these interactions under dynamic physiological conditions. Pharmacological profiling, including ADMET analysis, Lipinski's rule compliance, and bioactivity scoring, revealed favorable drug-like properties for both compounds, including strong absorption, distribution, low toxicity, and potential therapeutic activities such as enzyme inhibition and nuclear receptor-mediated processes. KEGG pathway enrichment analysis confirmed their involvement in key biological pathways linked to cancer progression, underscoring their therapeutic potential. The findings highlight curcumin and bis-demethoxycurcumin as promising phytochemical candidates for cancer therapy, capable of modulating MMP9 and GRP78 to suppress tumor progression. While these results provide a solid basis for their therapeutic potential, further experimental studies and clinical trials are crucial to confirm their efficacy and safety for human applications.

• MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• Curcuma * chemistry   metabolism   MeSH
• Diarylheptanoids pharmacology   MeSH
• Antineoplastic Agents, Phytogenic * pharmacology   chemistry   MeSH
• Curcumin analogs & derivatives   pharmacology   chemistry   MeSH
• Humans MeSH
• Matrix Metalloproteinase 9 * metabolism   chemistry   MeSH
• Neoplasms * drug therapy   metabolism   MeSH
• Drug Discovery * methods   MeSH
• Rhizome * chemistry   metabolism   MeSH
• Heat-Shock Proteins * metabolism   chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endoplasmic Reticulum Chaperone BiP MeSH
• demethoxycurcumin MeSH Browser
• Diarylheptanoids MeSH
• Antineoplastic Agents, Phytogenic * MeSH
• HSPA5 protein, human MeSH Browser
• Curcumin MeSH
• Matrix Metalloproteinase 9 * MeSH
• MMP9 protein, human MeSH Browser
• Heat-Shock Proteins * MeSH

Influenza virus, an RNA virus of the Orthomyxoviridae family, is responsible for widespread seasonal epidemics that result in 3 to 5 million severe illnesses and more than half a million deaths annually. Given the persistent circulation of pandemic influenza variants and increasing resistance to available inhibitors, there is an urgent need for new antiviral drugs effective against various viral subtypes. Viral RNA-dependent RNA polymerase, essential for viral replication, has emerged as a promising drug target. The PA subunit with endonuclease function is especially interesting, as development of the highly potent baloxavir marboxil (Xofluza) validated its importance as a novel drug target. Flavonoids have long been studied for their anti-influenza activity but have only recently been recognized as endonuclease inhibitors. We previously identified luteolin and its glucoside derivate, orientin, as potent endonuclease inhibitors, with their binding illustrated by X-ray crystallography structures. Building on this, we employed a scaffold-hopping approach based on the luteolin structure to design structurally distinct compounds that resemble the flavonoid scaffold. Using an AlphaScreen binding assay, we identified 33 as a submicromolar PA inhibitor with low toxicity. We solved the crystal structure of the PA endonuclease-binding pseudoflavonoid 36, which has similar structure and inhibitory potency to 33. Furthermore, we identified 24, 33, 34 and 36 as inhibitors of influenza polymerase in a minireplicon luciferase reporter assay as well as inhibitors of live H1N1 virus infection in A549 human lung cells.

• Publication type
• Journal Article MeSH

Quinazolinone derivatives have emerged as promising scaffolds in antimicrobial drug discovery. This work focuses on the design, synthesis, and evaluation of novel quinazolinone-based compounds and predicts their potential to interact with mycobacterial penicillin-binding proteins (PBPs). Relying on established structure-activity relationships of antibacterial quinazolinones, a total of 53 compounds belonging to three different structural types are synthesized and biologically evaluated for antimycobacterial, antibacterial, and antifungal activities. Biological evaluations reveal selective efficacy against Mycobacterium tuberculosis with minimum inhibitory concentrations (MICs) as low as 6.25 μg mL-1 for some derivatives, and this activity is preserved against drug-resistant strains. Molecular docking studies suggest a potential allosteric binding site in mycobacterial PBP 1A (PonA1, UniProt ID: P71707), and subsequential molecular dynamics confirm stable binding with key stabilizing interaction between the carbonyl oxygen of the quinazolinone and either ARG399 or ASP474. These findings suggest quinazolinone derivatives as viable candidates for further development as non-β-lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.

• Keywords
• antimycobacterial, computational chemistries, drug designs, medicinal chemistries, multidrug‐resistant tuberculosis, penicillin‐binding proteins, quinazolinones,
• MeSH
• Antifungal Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Antitubercular Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Quinazolinones * pharmacology   chemical synthesis   chemistry   MeSH
• Microbial Sensitivity Tests MeSH
• Drug Resistance, Multiple, Bacterial drug effects   MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis * drug effects   metabolism   MeSH
• Penicillin-Binding Proteins * antagonists & inhibitors   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antifungal Agents * MeSH
• Antitubercular Agents * MeSH
• Quinazolinones * MeSH
• Penicillin-Binding Proteins * MeSH