Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy

Journal of Biomolecular Structure and Dynamics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 19

Published: Jan. 24, 2025

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and (TDO) are reported promising novel targets cancer immunotherapy. IDO1 TDO overexpression TNBC cells promote resistance cell death, proliferation, invasion, metastasis. To date, there no clinically available small-molecule inhibitors that target these enzymes. Navoximod, reliable dual-specific inhibitor, resulted poor bioavailability modest efficacy clinical trials restricts its utility. This situation urges the development of potent drug-like candidate against A total 1574 natural compounds were proclaimed subjected ADME screening. Subsequently, resultant attributed hierarchical molecular docking MM-GBSA validation. Ultimately, re-scoring with aid combined machine learning algorithms six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among In addition, scaffold analysis also highlighted chromanone moiety hit compound boasts anti-cancer activity breast lines. reliability results was corroborated through rigorous 100 ns dynamics simulation using parameters including RMSD, PCA FEL analysis. light findings, it presumed proposed exhibits significant inhibitory activity. As result, we speculate further optimisation could be beneficial for treatment management TNBC.

Language: Английский

---

Integrated computational modeling and in-silico validation of flavonoids-Alliuocide G and Alliuocide A as therapeutic agents for their multi-target potential: Combination of molecular docking, MM-GBSA, ADMET and DFT analysis

South African Journal of Botany, Journal Year: 2024, Volume and Issue: 169, P. 276 - 300

Published: April 28, 2024

Language: Английский

---

Recent Advancements of Aptamers in Cancer Therapy

ACS Omega, Journal Year: 2023, Volume and Issue: 8(36), P. 32231 - 32243

Published: Aug. 30, 2023

Aptamers are chemical antibodies possessing the capability of overcoming limitations posed by conventional antibodies, particularly for diagnostic, therapeutic, and theranostic applications in cancer. The ease modifications or functionalization, including conjugations with nucleic acids, drug molecules, nanoparticles, has made these aptamers to gain priorities research. In this Mini-review, various reports on therapeutics aptamer-functionalized nanomaterials controlled multistep release, targeted delivery, stimuli-responsive etc. discussed. case nucleic-acid-conjugated aptamers, DNA nanotrains beacons discussed terms possibility multidrug loading chemotherapy gene therapy. Developments electrochemical aptasensors signal-enhanced immune also Further, future scope aptamer technology cancer theranostics prevailing

Language: Английский

---

Click-derived multifunctional metal complexes for diverse applications

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(15), P. 5051 - 5087

Published: Jan. 1, 2023

Numerous complex architectures are possible through Click reactions which display high specificity, flexibility and modularity. chemistry has addressed many challenges in the biomedical field, including drug delivery theranostics.

Language: Английский

---

Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(3), P. e0299238 - e0299238

Published: March 14, 2024

Background Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and albopictus . The RdRp protease of dengue virus potential therapeutic target. This study focused on the in silico drug discovery inhibitors. Methods To assess inhibitory activity 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, range computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, molecular dynamics (MD) simulations. aim these studies was to confirm stability ligand-protein complex binding pose identified during docking experiment. Results Twenty-one compounds found have possible activities DENV according data, they had affinity ≥-37.417 kcal/mol DENV3- enzyme as compared reference compound panduratin A. Additionally, investigation produced four hit that subjected screening obtain lead compound, catechin. Based ELUMO, EHOMO, band energy gap, DFT calculations showed strong electronegetivity, favouravle global softness chemical reactivity with considerable intra-molecular charge transfer between electron-donor electron-acceptor groups MD simulation result also demonstrated favourable RMSD, RMSF, SASA H-bonds at pocket catechin Conclusion According present findings, high sufficient drug-like properties appropriate profiles. Moreover, further supported action candidate. Therefore, vitro vivo research cocoa its phytochemical should be taken into consideration develop inhibitor.

Language: Английский

---

In silico and in vitro evaluation of novel carbothioamide-based and heterocyclic derivatives of 4-(tert-butyl)-3-methoxybenzoic acid as EGFR tyrosine kinase allosteric site inhibitors

Results in Chemistry, Journal Year: 2024, Volume and Issue: 7, P. 101329 - 101329

Published: Jan. 1, 2024

Cancer is an elaborate sequence of disease grades that include uncontrolled cell growth and division, invasion, metastasis. Overexpression the epidermal factor receptor (EGFR) causes abnormal signal transduction directly linked to cancer development. Most EGFR tyrosine kinase inhibitors (TKIs) are ATP-competitive frequently cause mutations or chemoresistance. Therefore, targeting TK allosteric site has become a highly sought after treatment strategy. Ten new derivatives 4-(tert-butyl)-3-methoxybenzoic acid containing carbothioamide (compounds 3a-e), triazole 4a-d) oxadiazole (compound 5) moieties were designed as deduced in silico. The structures these characterized by chemical spectroscopic methods (ATR-FTIR, 1HNMR, 13CNMR HRESI-MS). According molecular docking studies, compounds 3e 3d showed highest scores (ΔG), which was confirmed dynamic (MD) simulation studies. synthesized derivatives, specifically 3e, exhibited favorable pharmacokinetic profile. In vitro, newly evaluated for their cytotoxicity against A549 (lung adenocarcinoma), HepG2 (hepatocellular carcinoma), HCT-116 (colorectal) lines via MTT assay, flow cytometry, RT-PCR, immunoblotting, inhibition assay. results compound cytotoxic three tested lines, achieving lowest IC50 concentration cells. Compound caused cycle arrest at G2/M phase induction ER-mediated apoptosis pathway. silico vitro antitumor activity findings demonstrated it promising inhibitor.

Language: Английский

---

Ligand-based drug design against Herpes Simplex Virus-1 capsid protein by modification of limonene through in silico approaches

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 29, 2024

The pharmacological effects of limonene, especially their derivatives, are currently at the forefront research for drug development and discovery as well structure-based design using huge chemical libraries already widespread in early stages therapeutic development. Here, various limonene derivatives studied computationally potential utilization against capsid protein Herpes Simplex Virus-1. Firstly, were designed by structural modification followed conducting a molecular docking experiment In this research, obtained score exhibited better efficiency Virus-1 hence we conducted further silico investigation including dynamic simulation, quantum calculation, ADMET analysis. Molecular has documented that Ligands 02 03 had much binding affinities (- 7.4 kcal/mol - 7.1 kcal/mol) to than Standard Acyclovir 6.5 kcal/mol). Upon investigation, primary observed be slightly poor. But functional groups also increases capacity prevent viral infection Then, simulation confirmed mentioned ligands might stable during formation drug-protein complexes. Finally, analysis was essential establishing them safe human-useable prospective chemicals. According present findings, promising candidate which ultimately inhibits Virus-induced encephalitis causes interventions brain inflammation. Our findings suggested experimental screening determine practical value utility.

Language: Английский

---

Targeting Glucosylceramide Synthase: Innovative Drug Repurposing Strategies for Lysosomal Diseases

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2195 - 2195

Published: Feb. 28, 2025

Sphingolipidoses, a subgroup of lysosomal storage diseases (LSDs), are rare and debilitating disorders caused by defects in sphingolipid metabolism. Despite advancements treatment, therapeutic options remain limited. Miglustat, glucosylceramide synthase EC 2.4.1.80 (GCS) inhibitor, is one the few available pharmacological treatments; however, it associated with significant adverse effects that impact patients’ quality life. Drug repurposing offers promising strategy to identify new agents from approved drugs, expanding treatment for limited alternatives. This study aims potential alternative inhibitors GCS through drug-repurposing approach, using computational experimental methods assess their sphingolipidoses. A library drugs was screened advanced techniques, including molecular docking, dynamics simulations, metadynamics, inhibitors. Promising candidates were selected further vitro validation evaluate inhibitory activity as alternatives Miglustat. Computational screening identified several inhibitors, Dapagliflozin emerging most candidate. Experimental confirmed its efficacy, revealing complementary mechanism action Miglustat while potentially offering more favorable side effect profile. underscores utility methodologies drug diseases. The identification inhibitor provides foundation preclinical clinical evaluation, supporting application

Language: Английский

---

Synthetic access to diverse thiazetidines via a one-pot microwave assisted telescopic approach and their interaction with biomolecules

Organic & Biomolecular Chemistry, Journal Year: 2024, Volume and Issue: 22(16), P. 3249 - 3261

Published: Jan. 1, 2024

A one-pot microwave assisted telescopic approach is reported for the chemo-selective synthesis of substituted 1,3-thiazetidines using readily available 2-aminopyridines/pyrazines/pyrimidine, isothiocyanates and 1,2-dihalomethanes. The procedure involves thiourea formation from 2-aminopyridines/pyrazines/pyrimidine with followed by a base catalysed nucleophilic attack CS bond on 1,2-dihalomethane. Subsequently, cyclization reaction occurs to yield 1,3-thiazetidines. These four membered strained ring systems are possess broad substrate scope high functional group tolerance. above synthetic sequence heterocycles proven be modular straightforward approach. Further mechanistic pathway was supported computational evaluations X-ray crystallography analyses. relevance these thiazetidines in biological applications evaluated studying their ability bind bio-macromolecules like proteins nucleic acids.

Language: Английский

---

Secondary metabolites of Trichoderma spp. as EGFR tyrosine kinase inhibitors: Evaluation of anticancer efficacy through computational approach

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(1), P. e0296010 - e0296010

Published: Jan. 24, 2024

The present study explores the epidermal growth factor receptor (EGFR) tyrosine kinase inhibition efficacy of secondary metabolites in Trichoderma spp. through molecular docking, dynamics (MD) simulation and MM-PBSA approach. result docking confirmed that out 200 screened, three such as Harzianelactone A, Pretrichodermamide G Aspochalasin M, potentially bound with active binding site EGFR domain(PDB ID: 1M17) a threshold score ≤– 9.0 kcal/mol when compared standard inhibitor (Erlotinib). MD was run to investigate potential for stable complex formation domain-unbound/lead metabolite (Aspochalasin M)-bound/standard (Erlotinib)-bound complex. analysis at 100 ns revealed M formed EGFR. Besides, silico predication pharmacokinetic properties further qualified drug-likeness rules no harmful side effects ( viz ., hERG toxicity, hepatotoxicity skin sensitization), non-mutagenicity favourable logBB value. Moreover, BOILED-Egg model predicted showed higher gastrointestinal absorption improved bioavailability administered orally removed from central nervous system (CNS). results computational studies concluded possessed significant EGFR’s sites known Therefore, can be used possible anticancer drug candidate vitro vivo experimental validation are required determine its potential.

Language: Английский

---