Exploration of CviR-mediated quorum sensing inhibitors from Cladosporium spp. against Chromobacterium violaceum through computational studies

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Sept. 19, 2023

An opportunistic human pathogenic bacterium, Chromobacterium violaceum resists the potency of most antibiotics by exploiting quorum sensing system within their community to control virulence factor expression. Therefore, blocking mechanism could help treat several infectious caused this organism. The receptor (CviR) C. was used as a model target in current investigation identify potentially novel inhibitors from Cladosporium spp. through silico computational approaches. molecular docking results confirmed anti-quorum potential bioactive compounds binding CviR with varying scores between - 5.2 and 9.5 kcal/mol. Relative positive [Azithromycin (- 7.4 kcal/mol)], top six metabolites had higher were generally greater than 8.5 thermodynamic stability affinity refinement top-ranked further studied 160 ns dynamic (MD) simulation. Post-MD simulation analysis compounds' affinity, stability, biomolecular interactions at 50 ns, 100 Coniochaetone K having highest free energy 30.87 kcal/mol) best (two consistent hydrogen bond contact) following predicted pharmacokinetics properties selected point drug likeliness, potentiating chance possible candidate. Overall, spp., especially K, be identified inhibitors. development these broad-spectrum antibacterial medicines is thus future completion preclinical clinical research.

Language: Английский

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Computational exploration of Picrasma quassioides compounds as CviR-mediated quorum sensing inhibitors against Chromobacterium violaceum

Frontiers in Chemistry, Journal Year: 2024, Volume and Issue: 12

Published: May 28, 2024

Chromobacterium violaceum an opportunistic human pathogenic bacterium, exhibits resistance to conventional antibiotics by exploiting its quorum sensing mechanism regulate virulence factor expression. In light of this, disrupting the presents a promising avenue for treating infections caused this pathogen. The study focused on using cytoplasmic receptor CviR from C. as model target identify novel inhibitors P. quassioides through in silico computational approaches. Molecular docking analyses unveiled that several phytochemicals derived Picrasma exhibit potential inhibit binding protein. Notably, compounds such Quassidine I (– 8.8 kcal/mol), J Kumudine B 9.1 kcal/mol) and Picrasamide A 8.9 exhibited high scores, indicating strong affinity native ligand C6-HSL (N-hexanoyl-L-homoserine lactone) positive control/co-crystal inhibitor also demonstrated significant energy of—7.7 kcal/mol. molecular dynamics simulation 200 ns showed thermodynamic stability refinement top-ranked (Kumudine B) with stable minor fluctuations compared control (C6-HSL). Pharmacokinetic predictions indicated possesses favourable drug-like properties, which suggest drug candidate. highlight agent inhibiting protein . comprehensive evaluation provides valuable insights into pharmacological profiles, facilitating assessment diverse therapeutic applications guiding future research activities, particularly antibacterial agents clinical development.

Language: Английский

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Unveiling the anticancer potential and toxicity of Ganoderma applanatum wild mushroom derived bioactive compounds: An in vitro, in vivo and in silico evaluation

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108233 - 108233

Published: Feb. 1, 2025

Language: Английский

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Integrated Computational and Experimental Insights Into MEK1/2 Inhibitors: Structural Validation, Docking, ADMET, Molecular Dynamics, and Anticancer Evaluation

Chemistry & Biodiversity, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

This study explores the therapeutic potential of novel MEK1/2 inhibitors targeting MAPK pathway, emphasizing their critical role in cancer progression. An integrated computational approach, including molecular docking, pharmacophore modeling, dynamics simulations, and DFT analysis, was employed to evaluate binding affinity, stability, pharmacological properties FDA-approved experimental compounds. Structural validation MEK1 (PDB ID: 1S9J) MEK2 1S9I) revealed z-scores -6.89 -7.13, respectively, with 90.6% 86.7% residues most favored regions, confirming reliability protein models. Docking studies identified RO5126766 as a lead compound, exhibiting energies -10.1 kcal/mol -9.5 MEK2. Molecular simulations further demonstrated stability RO5126766-MEK1 RO5126766-MEK2 complexes, RMSD values ranging from 0.95 4.22 Å. The vitro anticancer assays highlighted exceptional potency RO5126766, IC50 12.87 ± 98.36 nM against MCF-7 (hormone receptor-positive breast cancer), 15.08 94.36 MDA-MB-231 (triple-negative 60.89 70.58 A549 (lung cancer). ADMET analysis confirmed high gastrointestinal absorption, favorable drug-likeness, lack blood-brain barrier permeability. In addition, indicated an optimal HOMO-LUMO energy gap (0.15816 eV), chemical hardness (0.16189 strong interactions corroborated by MEP analysis. Collectively, these findings establish potent selective inhibitor, demonstrating significant targeted agent for aggressive treatment-resistant cancers.

Language: Английский

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Molecular screening and dynamics simulation reveal potential phytocompounds in Swertia chirayita targeting the UspA1 protein of Moraxella catarrhalis for COPD therapy

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0316275 - e0316275

Published: Feb. 28, 2025

Chronic obstructive pulmonary disease (COPD) is a global health burden, with Moraxella catarrhalis significantly contributing to acute exacerbations and increased healthcare challenges. This study aimed identify potential drug candidates in Swertia chirayita , traditional Himalayan medicinal plant, demonstrating efficacy against the ubiquitous surface protein A1 (UspA1) of M. through an in-silico computational approach. The three-dimensional structures 46 phytocompounds S. were retrieved from IMPPAT 2.0 database. underwent thorough analysis screening, emphasizing key factors such as binding energy, molecular docking performance, drug-likeness, toxicity prediction assess their therapeutic potential. Considering spectrometry, pharmacokinetic properties, results, likeliness, toxicological effects, five beta-amyrin, calendol, episwertenol, kairatenol swertanone identified inhibitors UspA1 . demonstrated affinities –9.1 kcal/mol for –8.9 –9.4 –9.6 kairatenol, –9.0 swertanone. All these stronger than that control ceftobiprole, which had score –6.6 kcal/mol. confirmed all compounds are safe options, showing no or carcinogenicity. We also performed 100 ns dynamics simulation analyze stability interactions protein-ligand complexes. Among screened phytocompounds, beta-amyrin episwertenol exhibited favorable characteristics, including stable root mean square deviation values, minimal fluctuations, consistent radius gyration values. Throughout simulations, intermolecular hydrogen bonds hydrophobic contacts maintained. Additionally, strong affinity, indicated by negative free energy Taken together, findings this strongly suggest have act offering promising prospects treatment management COPD.

Language: Английский

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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

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Exploration of Type III effector Xanthomonas outer protein Q (XopQ) inhibitor from Picrasma quassioides as an antibacterial agent using chemoinformatics analysis

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(6), P. e0302105 - e0302105

Published: June 18, 2024

The present study was focused on exploring the efficient inhibitors of closed state (form) type III effector Xanthomonas outer protein Q (XopQ) (PDB: 4P5F) from 44 phytochemicals Picrasma quassioides using cutting-edge computational analysis. Among them, Kumudine B showed excellent binding energy (−11.0 kcal/mol), followed by Picrasamide A, Quassidine I and J with targeted XopQ compared to reference standard drug (Streptomycin). molecular dynamics (MD) simulations performed at 300 ns validated stability top lead ligands (Kumudine B, I)-bound complex slightly lower fluctuation than Streptomycin. MM-PBSA calculation confirmed strong interactions QuassidineI) protein, as they offered least energy. results absorption, distribution, metabolism, excretion, toxicity (ADMET) analysis that I, A were found qualify most drug-likeness rules bioavailability scores Results studies suggested could be considered potential compounds design novel antibacterial drugs against X . oryzae infection. Further in vitro vivo activities are required confirm their therapeutic potentiality controlling

Language: Английский

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The combination of multi-approach studies to explore the potential therapeutic mechanisms of imidazole derivatives as an MCF-7 inhibitor in therapeutic strategies

Frontiers in Chemistry, Journal Year: 2023, Volume and Issue: 11

Published: June 27, 2023

Breast cancer covers a large area of research because its prevalence and high frequency all over the world. This study is based on drug discovery against breast from series imidazole derivatives. A 3D-QSAR activity atlas model was developed by exploring dataset computationally, using machine learning process Flare. The compounds divided into active inactive according to their biological structural similarity with reference drug. obtained PLS regression provided an acceptable r2 = 0.81 q2 0.51. Protein-ligand interactions molecules were shown molecular docking six potential targets, namely, TTK, HER2, GR, NUDT5, MTHFS, NQO2. Then, toxicity risk parameters evaluated for hit compounds. Finally, after these screening processes, compound C10 recognized as best-hit compound. identified new inhibitor evidence-based knowledge discover more analogs.

Language: Английский

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Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Frontiers in Chemistry, Journal Year: 2023, Volume and Issue: 11

Published: June 7, 2023

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cases. TrkA represents an attractive target for treatment; however, currently available inhibitors face limitations in terms resistance development and potential toxicity. Hence, objective this study was identify new allosteric-approved can overcome these challenges be employed therapy. To achieve goal, a screening 9,923 drugs from ChEMBL database conducted assess their repurposing using molecular docking. The top 49 drug candidates, exhibiting highest docking scores (-11.569 -7.962 kcal/mol), underwent MM-GBSA calculations evaluate binding energies. Delanzomib tibalosin, two -10.643 -10.184 kcal/mol, respectively, along dG bind values -67.96 -50.54 were subjected 200 ns dynamic simulations, confirming stable interactions TrkA. Based on findings, we recommend further experimental evaluation delanzomib tibalosin determine as allosteric These provide more effective less toxic therapeutic alternatives. approach study, which involves through dynamics, serves valuable tool identifying novel candidates distinct uses. This methodology contribute reducing attrition rate expediting process discovery.

Language: Английский

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Friedelin: Structure, Biosynthesis, Extraction, and Its Potential Health Impact

Molecules, Journal Year: 2023, Volume and Issue: 28(23), P. 7760 - 7760

Published: Nov. 24, 2023

Pharmaceutical companies are investigating more source matrices for natural bioactive chemicals. Friedelin (friedelan-3-one) is a pentacyclic triterpene isolated from various plant species different families as well mosses and lichen. The fundamental compounds of these friedelane triterpenoids abundantly found in cork tissues leaf materials diverse genera such Celastraceae, Asteraceae, Fabaceae, Myrtaceae. They possess many pharmacological effects, including anti-inflammatory, antioxidant, anticancer, antimicrobial activities. also has an anti-insect effect the ability to alter soil microbial ecology, making it vital agriculture. Ultrasound, microwave, supercritical fluid, ionic liquid, acid hydrolysis extract friedelin with reduced environmental impact. Recently, high demand led development CRISPR/Cas9 technology gene overexpression plasmids produce using genetically engineered yeast. low cytotoxicity normal cells can be best phytochemical drug choice. review summarizes structural interpretation, biosynthesis, physicochemical properties, quantification, forms significance.

Language: Английский

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