Search Results (529)

Background: Chemotherapy is a cornerstone of cancer treatment; however, resistance to first-line chemotherapeutic agents remains a major challenge. ROS1, one of fifty-eight receptor tyrosine kinases, has been implicated in various cancer subtypes, including glioblastoma, non-small-cell lung cancer, and cholangiocarcinoma. Notably, the Gly2032Arg mutation in the ROS1 protein has been linked to resistance against the kinase inhibitor crizotinib. Objectives: Given the challenge, we conducted a comprehensive in silico study to identify new drug candidates. Methods: The study starts with modeling the Gly2032Arg-mutated ROS1 protein, followed by structure-based screening of the PubChem database. Results: Out of 1760 molecules screened, we selected the top 4 molecules (PubChem CID: 67463531, 72544946, 139431449, and 139431487) with structural features similar to crizotinib, a high docking score, and drug likeness. To further validate the effectiveness of the identified compounds, we assessed their binding affinity using the Molecular Mechanics with Generalized Born Surface Area (MM-GBSA) scoring method. To underpin the behavior and stability of protein–ligand complexes, 500 ns molecular dynamics (MD) simulations were conducted, and parameters including RMSD, RMSF, and H-bond dynamics were studied and compared. Density functional theory (DFT) at the B3LYP/6-31G* level was performed to elucidate molecular features of the identified compounds. Conclusions: Overall, this study sheds light on a new series of compounds effective against mutated targets, thereby offering a new horizon in this area. Full article

Background/Objective: The primary cilium is the sensory organelle of a cell and a dynamic membrane protrusion during the cell cycle. It originates from the centriole at G₀/G₁ and undergoes disassembly to release centrioles for spindle formation before a cell enters mitosis, thereby serving as a cell cycle checkpoint. Cancer cells that undergo rapid cell cycle and replication have a low ciliation rate. In this study, we aimed to identify cilia-promoting drugs that can accelerate ciliation and decelerate replication of cancer cells. Methods: To perform a comprehensive and efficient literature search on drugs that can promote ciliation, we developed an intelligent process that integrates either the GPT 4 Turbo, Gemini 1.5 Pro, or Claude 3.5 Haiku application programming interfaces (APIs) into a PubMed scraper that we coded, enabling the large language models (LLMs) to directly query articles for predefined user questions. We evaluated the performance of this intelligent literature search based on metrics and tested the effect of two candidate drugs on ciliation and proliferation of medulloblastoma cells. Results: Gemini was the best model overall, as it balanced high accuracy with solid precision and recall scores. Among the top candidate drugs identified are Alvocidib and Alisertib, small-molecule inhibitors of CILK1 and AURKA, respectively. Here, we show that both kinase inhibitors can effectively increase cilia frequency and significantly decrease the replication of medulloblastoma cells. Conclusions: The results demonstrated the potential of using cilia-promoting drugs, such as Alvocidib and Alisertib, to suppress cancer cell replication. Additionally, it shows the massive benefits of integrating accessible large language models to conduct sweeping, rapid, and accurate literature searches. Full article

Background/Objectives: The development of specific inhibitors for cyclooxygenase-2 (COX-2) is a challenge for public health. A series of 17 N-phthalimide hybrids was evaluated using a functional M06 meta-GGA hybrid in combination with a polarized 6-311G (d, p) basis set. The top three candidates (6, 10, and 17) were synthesized and evaluated as selective COX-2 inhibitors of PGE-2 using an integrated in silico–in vitro approach. Methods: Molecular docking against COX-2 (PDB 5KIR) and COX-1 (PDB 6Y3C), supported by homology modeling and DFT geometry optimization (B3LYP/6-31G*), revealed that the phthalimide carbonyl groups and the 3,4,5-trimethoxyphenyl or geranyl-derived moieties establish key hydrogen bonds and hydrophobic contacts with Arg120, Tyr355, Tyr385, and Ser530 in the COX-2 active site, conferring predicted selectivity ΔGCOX−2 vs. COX−1 = −1.4 to −2.8 kcal/mol. Results: The compounds complied with Lipinski’s and Veber’s rules and displayed favorable ADMET profiles. In vitro assessment in LPS-stimulated J774A.1 murine macrophages confirmed potent inhibition of PGE₂ production, 3.05 µg/mL, with compound 17 exhibiting the highest efficacy, 97.79 ± 5.02% inhibition at 50 µg/mL, and 10 showing 95.22 ± 6.03% inhibition at 50 µg/mL. Notably, all derivatives maintained >90% cell viability up to 250 µg/mL by resazurin assay and showed no evidence of cytotoxicity or mitosis potential in the tests at 24 h. Conclusions: These results demonstrate that strategic hybridization of phthalimide with natural and synthetic product-derived fragments yields highly potential PGE2 inhibitors. Therefore, compounds 6, 10, and 17 are promising lead candidates for the development of safer anti-inflammatory agents. Full article

Background/Objectives: Obstructive sleep apnea (OSA) affects approximately 1 billion adults worldwide with extensive comorbidities, including cardiovascular disease, metabolic disorders, and cognitive decline, yet pharmacological therapies remain limited. Conventional bottom-up omics approaches identify numerous genes overlapping with other diseases, hindering therapeutic translation. This study introduces a top-down, comorbidity-driven approach to identify actionable molecular targets and develop rational dual kinase inhibitors for OSA management. Methods: We implemented a five-tier modeling workflow: (1) comorbidity network analysis, (2) disease module identification through NetworkAnalyst, (3) mechanistic pathway reconstruction of the CK1δ-(HIF1A)-PINK1 signaling cascade, (4) molecular docking analysis of Nigella sativa alkaloids and reference inhibitors (IC261, PF-670462) against CK1δ (PDB: 3UYS) and PINK1 (PDB: 5OAT) using AutoDock Vina, and (5) rational design and computational validation of novel dual inhibitors (ICL, PFL) integrating pharmacophoric features from natural alkaloids and established kinase inhibitors. Results: Extensive network analysis revealed a discrete OSA disease module centered on two interconnected protein kinases—CK1δ and PINK1—that mechanistically bridge circadian disruption and neurodegeneration. Among natural alkaloids, Nigellidine showed strongest CK1δ binding (−8.0 kcal/mol) and Nigellicine strongest PINK1 binding (−8.6 kcal/mol). Rationally designed dual inhibitors demonstrated superior binding: ICL (−7.2 kcal/mol PINK1, −8.9 kcal/mol CK1δ) and PFL (−10.8 kcal/mol CK1δ, −11.2 kcal/mol PINK1), representing −2.6–2.8 kcal/mol improvements over reference compounds. Conclusions: This study establishes a comorbidity-driven translational framework identifying the CK1δ-PINK1 axis as a therapeutic target in OSA. The rationally designed dual inhibitors represent third-generation precision therapeutics addressing OSA’s multi-dimensional pathophysiology, while the five-tier workflow provides a generalizable template for drug discovery in complex multimorbid diseases. Full article

To identify pancoronaviral inhibitors, we sought to identify peptides that bound the evolutionarily conserved SARS-CoV-2 spike fusion peptide (FP). We screened the NEB PhD-7-mer random combinatorial phage display library against FP, synthesised as a D-peptide, to identify peptides from the L-library to be synthesised as proteolytically resistant D peptides. We selected the top ten peptides that were not seen in another published screen with this library, as these were more likely to be specific. All ten D-peptides had no impact on the infection of Vero-E6/TMPRSS2 cells by SARS-CoV-2. Screening of a proteomic-derived phage display library from the disordered regions of human proteins identified two overlapping 14mer peptides from a region of OTUD1. While a synthetic peptide based on their sequences failed to markedly inhibit viral entry, molecular dynamics structural modelling highlighted a stable binding mode where positive residues on one side of the OTUD1 helix interacted with hydrophobic residues of the FP triple-helical wedge. Thus, while the two phage display strategies failed to yield peptide sequences that are themselves strong inhibitors of viral infection, they led to the development of a computational model that can underpin future designs of potential pancoronaviral FP disruptors. Full article

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol’s reliability. Results: The top compounds—H7, H10 and H11—showed potent cruzain inhibition (IC₅₀ = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC₅₀ > 64 µM) and favorable selectivity. Structure–activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1′ subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain. Full article

Eosinophilic esophagitis (EoE) is a chronic, allergic, immune-mediated inflammation of the esophagus caused by food antigens. The prevalence in pediatric population is approximately 34 to 57 cases per 100,000 children, with a male to female ration 3:1. This number may be underestimated due to diagnostic challenges and variety of clinical presentations in different age groups. Diagnosis of EoE requires histopathological assessment of esophageal biopsies retrieved during gastroscopy, with at least 15 eosinophils per high-power field (HPF) in the esophageal tissue being the cut off value. According to recommendations, treatment options of EoE include dietary interventions (elimination diets), medical treatment (inhibitors of proton pump, steroids, biologics), and in some cases surgical intervention (dilation). Dietary intervention, such as elimination diets, target the triggering factors of the disease and, if supervised by professional nutritionist, have the least systemic side effects. On the other hand, depending on the number of allergens eliminated from the pediatric patients’ diet, the quality of life both of the child and their caretakers may be compromised. Additional challenges such as nutritional risks, feeding disorders, financial burden, and social life impairment also have to be taken into consideration. On top of this, an effectiveness assessment of chosen therapy requires repeated endoscopic examination with several biopsies of the esophagus, further increasing diseases burden in EoE patients. Taking all of this factors into consideration, the main objective of this narrative review was to address challenges that pediatric patients with EoE on dietary treatment face with reference to current research and daily practice. Full article

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Background/Objectives: Cutaneous adverse drug reactions (CADRs) represent the most common manifestations of drug-induced allergy, with most unfavorable clinical outcomes seen in severe cutaneous adverse reactions (SCARs). To manage SCARs immediate cessation of the offending drug is needed; therefore, it is crucial to identify the list of medications associated with SCARs in real-world clinical practice. The objective of this study was to evaluate the structure of drugs associated with SCARs and to analyze drug-induced SCAR signals by calculating the reporting odds ratio (ROR) and proportional reporting ratio (PRR) based on spontaneous reports extracted from the Russian national pharmacovigilance database. Methods: A retrospective, descriptive pharmacoepidemiological analysis of spontaneous reports (SRs) registered in the pharmacovigilance database from 1 April 2019 to 31 March 2025. Results: A total of 7011 SRs with SCARs were finally revealed, with 907 identified drug triggers. The most frequently reported were antibacterial drugs for systemic use (22.8%), antineoplastic agents (17.8%), and antiepileptics (6.0%). The top five drugs involved in SCARs were dupilumab (2.14%, n = 244), piperacillin and beta-lactamase inhibitor (2.0%, n = 227), pembrolizumab (1.98%, n = 225), levofloxacin (1.95%, n = 222), and linagliptin (1.93%, n = 220). The strongest signals were detected for linagliptin (PRR = 15.37, 95% CI: 13.54–17.44; ROR = 17.24, 95% CI: 14.95–19.88), followed by clindamycin (PRR = 12.44, 95% CI: 10.89–14.21; ROR = 13.62, 95% CI: 11.77–15.77) and by piperacillin and beta-lactamase inhibitor (PRR = 10.02, 95% CI: 8.86–11.43; ROR = 10.81, 95% CI: 9.42–12.40). Conclusions: Pharmacovigilance databases facilitate the identification of diverse phenotypes of SCARs and the list of culprit drugs. The accumulated data serve as a valuable tool to enhance clinical practice outcomes and strengthen overall healthcare monitoring. Full article

Bacterial blight in rice, caused by Xanthomonas oryzae pv. oryzae (Xoo), poses a serious threat to global rice production. The ability of Xoo to form biofilms is a key factor for its virulence. The OryR protein is a LuxR-type quorum-sensing regulator essential for biofilm formation and Xoo pathogenicity. However, the three-dimensional structure of OryR remains poorly understood. This study integrates homology modeling, molecular dynamics (MD) simulations, and virtual screening to elucidate the structure of OryR and identify potential inhibitors that target its ligand-binding domain. MD simulations confirmed the structural stability of OryR, and comparative analysis with experimentally determined structures of ligand- or inhibitor-bound homologs revealed a binding site in OryR with a distinct hourglass-like shape for long-range contacts. Virtual screening of over 200,000 compounds from four chemical libraries identified several promising inhibitor candidates, with the top compounds showing strong binding energies in both molecular mechanics-generalized Born surface area (−68.3 kcal/mol) and molecular mechanics Poisson–Boltzmann surface area (−19.3 kcal/mol) calculations. Overall, this study provides insights into the OryR structure and highlights potential inhibitors that can be developed as novel agents to control bacterial blight. However, additional experimental validations are required to refine and optimize these leads for drug development. Full article

Background/Objective: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques, derived from the amyloid precursor protein through sequential cleavage by β-secretase 1 (BACE-1) and γ-secretase. BACE-1 is therefore a key drug target for designing of selective inhibitors to avoid off-target effects associated with BACE-2 inhibition. The objective of this study was to design novel BACE-1 inhibitors using a structure-based drug design approach. Methods: A focused compound library was designed based on the SAR of N-(4-fluorophenyl)formamide derivatives. In silico ADME predictions were performed to assess pharmacokinetic suitability. Compounds showing favorable ADME profiles were subjected to molecular docking against the BACE-1 enzyme. The top-scoring hit, compound 9.7 (−5.48 (kcal/mol), was further evaluated using a 200 ns MD simulation to assess the stability of its binding interactions with BACE-1. Results: Designed compounds indicated acceptable physicochemical and ADME characteristics. Molecular docking identified compound 9.7 as exhibiting favorable binding interactions with binding pocket residues of BACE-1. The 200 ns MD simulation further confirmed the stability of the docked complex. MD simulations confirmed that 9.7 forms stable interactions with the catalytic residue ASP32 and key hydrophobic residues TRP115 and PHE108 of BACE-1. These important interactions are absent in the reference compound verubecestat. Conclusions: The multi-step computational analysis suggests that compound 9.7 is a promising and selective BACE-1 inhibitor. Its favorable ADME profile, favorable docking interactions, and stable MD simulation behavior highlight its potential as a hit compound for further optimization in the development of anti-Alzheimer’s agents. Full article

In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CL^pro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CL^pro–inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CL^pro-IPCL complex (∆∆G_com) and the experimentally determined activities ${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$, which explained approximately 92% of the variation in the 3CL^pro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CL^pro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CL^pro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration ${IC}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CL^pro–inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues. Full article

Background: Radiation-induced pulmonary fibrosis (RPF) remains a major burden of successful lung cancer radiotherapy. Clinically validated drugs targeting RPF remains scarce. Methods: We employed a transcriptome-based drug repurposing approach using REMEDY, a computational platform built on the Library of Integrated Network-Based Cellular Signatures (LINCS). Differentially expressed genes (DEGs) derived from radiation-induced lung injury (RILI) models were used as a query to identify compounds capable of reversing pro-fibrotic expression profile. Among top-ranked candidates, homoharringtonine (HHT), an FDA-approved protein synthesis inhibitor, was selected for experimental validation. Anti-fibrotic effects of HHT were assessed using an optimized in vitro fibrotic model based on activation of MRC-5 human lung fibroblasts. Complementary in silico molecular docking analyses were also conducted to explore the mechanistic basis of HHT’s actions. This represents the first transcriptome-guided, LINCS-based drug repurposing study applied specifically to radiation-induced pulmonary fibrosis, utilizing RPF-derived molecular signatures rather than general fibrosis-related datasets. Results: HHT significantly attenuated key fibrotic phenotypes, including fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) production. Notably, HHT suppressed expression of cyclin D1 and α-smooth muscle actin (α-SMA), and reduced collagen deposition. Mechanistic investigations revealed that HHT modulates two pro-fibrotic pathways: RhoA/ROCK and Wnt/β-catenin signaling. Molecular docking further suggested that HHT may directly interact with fibrosis-related receptors such as integrins and Frizzled, providing structural insight into its anti-fibrotic potential. These findings underscore the novelty of reassigning HHT to a radiation-specific fibrotic context using a signature-reversal strategy uniquely tailored to RPF biology. Conclusions: Our findings identify HHT as a promising treatment of RPF, offering a dual mechanism of action—interruption of protein synthesis and targeted inhibition of fibrotic signaling pathways. This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT’s in vivo efficacy and clinical applicability in RPF. Full article

The proteasome β5 subunit plays a central role in protein degradation and is an established therapeutic target in glioblastoma. Marizomib (MZB), a natural β5 inhibitor, has shown promising anticancer activity, yet suboptimal pharmacological properties limit its clinical translation. Using a comprehensive computational approach, this study aimed to identify and characterize novel MZB analogs with improved binding affinity, stability, and drug-like profiles. An integrative in silico study was performed, including molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, molecular dynamics (MD) simulations over 200 ns, MM/PBSA binding free energy calculations, and per-residue energy decomposition. ADMET profiling evaluated the pharmacokinetic and safety properties of MZB and top-performing analogs. Docking and pharmacophore modeling revealed strong complementarity between MZB analogs and the β5 catalytic pocket. MD simulations showed that MZBMOD-77 and MZBMOD-79 exhibited exceptional structural stability with low RMSD values (0.40–0.42 nm), persistent binding within the active site cavity, and significant disruption of hydrogen-bond networks in the active loop regions Ala19–Lys33 and Val87–Gly98. MM/PBSA analysis confirmed their superior binding free energies (−19.99 and −18.79 kcal/mol, respectively), surpassing native MZB (−6.26 kcal/mol). Per-residue decomposition highlighted strong contributions from Arg19, Ala20, Lys33, and Ala50. ADMET predictions indicated improved oral absorption, reduced toxicity, and favorable pharmacokinetics compared to native MZB. This integrative computational study identifies MZBMOD-77 and MZBMOD-79 as promising next-generation proteasome β5 inhibitors. These analogs mimic and enhance the inhibitory mechanism of native MZB, offering potential candidates for further optimization and preclinical development in glioblastoma therapy. Full article