Design of novel anti-cancer agents targeting COX-2 inhibitors based on computational studies

Arabian Journal of Chemistry, Journal Year: 2023, Volume and Issue: 16(10), P. 105193 - 105193

Published: July 31, 2023

The overexpression of cyclooxygenase-2 (COX-2) was clearly associated with carcinogenesis, and COX-2 as a possible target has long been exploited for cancer therapy. A group 29 derivatives 1, 5-diarylpyrazole used to study its structural requirements using three-dimensional quantitative structure-activity relationship (3D-QSAR), the density functional theory method, molecular docking, dynamics. Four 3D-QSAR models were developed, predictive capability four selected also successfully tested different validation methods. contribution contours comparative field analysis (CoMFA) similarity index (CoMSIA) effectively illustrate relationships between various chemical characteristics their biological activities. Using method 6-31G (d, p) basis set Becke, 3-parameter, Lee-Yang-Parr (B3LYP) function evaluate reactivity properties, results obtained from energy gaps 3.431, 3.446, 2.727 ev molecules numbers 21, 22, 23 indicate that these three have good stability select most reactive regions in studied. Molecular docking revealed active sites protein (PDB code: 3PGH) residues ARG222, THR212, HIS386, HIS207, TYR148, ASP382, which ligands now can inhibit enzyme. Based on by modeling, new compounds (N1, N2, N3, N4) proposed significant predicted activity models. dynamics simulations (N1 N2) molecule over 100 ns all establish multiple hydrogen interactions several exhibit frequent throughout simulation period. As result, it is strongly recommended consider two newly molecules, N1 N4, promising candidates novel anti-cancer agents specifically designed inhibition.

Language: Английский

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An in-depth study of indolone derivatives as potential lung cancer treatment

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 16, 2025

Lung cancer is a type of that begins in the lungs and one leading causes cancer-related deaths worldwide. Herein an attempt to explore relationship between properties indolone derivatives their anticancer activity was investigated, implementing silico approaches. Four with highest potential were selected evaluate pharmacological properties. The ADMET analysis revealed these compounds exhibited favourable drug-like properties, meeting nearly all key criteria required for therapeutic agents. Molecular docking studies most active strong interactions critical amino acid residues PDK1 receptor's binding site, underscoring as effective inhibitors. In addition, 200 ns molecular dynamics (MD) simulations two R S configurations validated stability ligand-receptor complexes, minimal structural deviations observed throughout simulation period. These comprehensive results highlight viable drug candidates provide solid foundation future optimization efforts aimed at developing novel inhibitors therapy.

Language: Английский

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An in-silico investigation based on molecular simulations of novel and potential brain-penetrant GluN2B NMDA receptor antagonists as anti-stroke therapeutic agents

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(12), P. 6174 - 6188

Published: July 10, 2023

GluN2B-induced activation of NMDA receptors plays a key function in central nervous system (CNS) disorders, including Parkinson, Alzheimer, and stroke, as it is strongly involved excitotoxicity, which makes selective receptor antagonists one the potential therapeutic agents for treatment neurodegenerative diseases, especially stroke. The present study aims to examine structural family thirty brain-penetrating GluN2B N-methyl-D-aspartate (NMDA) antagonists, using virtual computer-assisted drug design (CADD) discover highly candidate drugs ischemic strokes. Initially, physicochemical ADMET pharmacokinetic properties confirmed that C13 C22 compounds were predicted non-toxic inhibitors CYP2D6 CYP3A4 cytochromes, with human intestinal absorption (HIA) exceeding 90%, designed be efficient due highest probability cross blood-brain barrier (BBB). Compared ifenprodil, co-crystallized ligand complexed transport protein encoded 3QEL.pdb, we have noticed chemical defined by good ADME-Toxicity profiles, meeting Lipinski, Veber, Egan, Ghose, Muegge rules. molecular docking results indicated ligands react specifically amino acid residues subunit GluN1 GluN2B. These intermolecular interactions produced between targeted B chain remain stable over 200 nanoseconds dynamics simulation time. In conclusion, are recommended anti-stroke their safety stability towards receptors.Communicated Ramaswamy H. Sarma

Language: Английский

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In-silico screening based on molecular simulations of 3,4-disubstituted pyrrolidine sulfonamides as selective and competitive GlyT1 inhibitors

Arabian Journal of Chemistry, Journal Year: 2023, Volume and Issue: 16(10), P. 105105 - 105105

Published: June 28, 2023

A systematic in silico study based on molecular modeling techniques was conducted thirty 3,4-disubstituted pyrrolidine sulfonamides derivatives to identify the drug candidate for treating schizophrenia and impairments associated with NMDA receptor hypofunction, through selective competitive inhibition of GlyT1. QSAR analysis demonstrates that geometric constitutional descriptors have a key function human GlyT1 activity. The in-silico concluded most active ligand labeled C19 predicted be non-toxic inhibitor, desired ADME-Toxicity profile significant probability penetrate central nervous system (CNS). Molecular docking simulations confirmed compound docked sites drosophila melanogaster dopamine transporter (DAT) protein, creating variety chemical bonds towards TYR 124, ASP 475, GLU 480, ALA 479, VAL 120 amino acids residues. dynamic (MD) technique combined MMGBSA approach produced intermolecular interactions (DAT protein–C19 ligand) complex remain so stable during 100 nanoseconds MD simulation time. Consequently, is highly recommended treatment other disabilities linked hypofunction glutaminergic receptors.

Language: Английский

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In silico insights into the design of novel NR2B-selective NMDA receptor antagonists: QSAR modeling, ADME-toxicity predictions, molecular docking, and molecular dynamics investigations

BMC Chemistry, Journal Year: 2024, Volume and Issue: 18(1)

Published: July 31, 2024

Abstract Based on a structural family of thirty-two NR2B-selective N-Methyl-D-Aspartate receptor (NMDAR) antagonists, two phenylpiperazine derivatives labeled C37 and C39 were conceived thanks to molecular modeling techniques, as novel NMDAR inhibitors exhibiting the highest analgesic activities (of pIC 50 order) against neuropathic pain, with excellent ADME-toxicity profiles, good levels stability towards targeted protein NMDA receptor. Initially, quantitative structure-activity relationships (QSARs) models developed using multiple linear regression (MLR), partial least square (PLSR), non-linear (MNLR), artificial neural network (ANN) revealing that activity was strongly correlated dipole moment, octanol/water partition coefficient, Oxygen mass percentage, electronegativity, energy lowest unoccupied orbital, whose correlation coefficients generated were: 0.860 , 0.758 0.885 0.977 respectively. The predictive capacity each model evaluated by an external validation 0.703 0.851 0.778 0.981 respectively, followed cross-validation technique leave-one-out procedure (CVLOO) Q 2 cv 0.785 more than Y-randomization test, applicability domain (AD), in addition Fisher’s Student’s statistical tests. Thereafter, ten molecules designed based MLR QSAR model, then predicted their ADME-Toxicity profiles subsequently examined for similarity drug candidates. Finally, most active compounds (C37 C39) chosen docking dynamics (MD) investigations during 100 ns MD simulation time complex (5EWJ.pdb).

Language: Английский

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Unveiling structural components of dibenzofuran-based MMP-12 inhibitors: a comparative classification-dependent analysis with molecular docking-based virtual screening and molecular dynamics simulation

In Silico Pharmacology, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 7, 2025

Language: Английский

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Molecular docking, dynamic molecular simulation and in silico ADMET screening study of novel bidentate tetrazolyl-adipate anti-HIV drugs candidate

CHINESE JOURNAL OF ANALYTICAL CHEMISTRY (CHINESE VERSION), Journal Year: 2025, Volume and Issue: unknown, P. 100498 - 100498

Published: Jan. 1, 2025

Language: Английский

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Exploring donor-acceptor characteristics and adsorption behavior of a naphthamide-based inhibitor for protective surfaces through a molecular modeling approach

Journal of the Indian Chemical Society, Journal Year: 2025, Volume and Issue: unknown, P. 101640 - 101640

Published: Feb. 1, 2025

Language: Английский

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Chemical profiling, safety assessment, bioactive properties, and molecular interactions of the essential oil derived from Mentha pulegium L.

Frontiers in Sustainable Food Systems, Journal Year: 2025, Volume and Issue: 9

Published: March 6, 2025

Mentha pulegium L., (MP) of the Lamiaceae family, endemic to Morocco, is a medicinal plant used in classical medicine. The aim present study enhance value this species by investigating chemical composition its essential oil (EO), antioxidant activity, toxicity, molecular docking and antimicrobial properties. In vitro measurement activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) reduction assay 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid; ABTS) demonstrated plant’s best performance. toxicity test reveals that EO non-toxic at an LD 50 2000 mg/kg rat body weight. Evaluation effect diffusion, direct contact, dilution sporulation methods showed all strains tested were sensitive MP EO. Minimal inhibitory concentration (MIC) minimum bactericidal (MBC) values for clinical ranged from 2 mg/mL 10 mg/mL. could therefore be good alternative treatment infectious diseases.

Language: Английский

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Design and evaluation of novel triazole derivatives as potential anti-gout inhibitors: a comprehensive molecular modeling study

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 13

Published: March 6, 2025

Gout is the most common inflammatory arthritis, characterized by hyperuricemia, tophus formation, joint disease, and kidney stones. Uric acid, final byproduct of purine catabolism, eliminated via kidneys digestive system. Xanthine oxidase (XO) catalyzes conversion hypoxanthine xanthine into uric making XO inhibitors crucial for treating hyperuricemia gout. Currently, three are clinically used, showing significant efficacy. A molecular modeling study on triazole derivatives aims to identify novel using 3D-QSAR, docking, MD simulations, ADMET analysis, DFT calculations. These computational approaches facilitate drug discovery while reducing research costs. Our work focuses a series synthesized anti-xanthine inhibitors, aiming develop new inhibitors. was carried out inhibitory structural features method. model based CoMFA CoMSIA/SEA has been built predict derivatives. The optimal established from successfully evaluated its predictive capability. Visualization contour maps both models showed that modifying substituents plays key role in enhancing biological activity anti-gout Molecular docking results complexes N°8-3NVY N°22-3NVY scores -7.22 kcal/mol -8.36 kcal/mol, respectively, indicating substantial affinity enzyme. Complex forms two hydrogen bonds with SER 69 ASN 71, alkyl ALA 70, LEU 74, 75, one Pi-Pi T-shaped bond PHE 68. HIS 99, ARG 29, ILE 91, halogen 128 at 3.60 Å. revealed complex remained highly stable throughout simulation. Therefore, we proposed six molecules, their activities were predicted models, they Lipinski's rule, properties. show Pred 4 5 have better pharmacokinetic properties than height potent molecule studied series, these compounds valuable candidates drugs. Subsequently, evaluate chemical reactivity compounds, energy gap molecules exhibit moderate stability reactivity.

Language: Английский

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