Design and evaluation of piperidine carboxamide derivatives as potent ALK inhibitors through 3D-QSAR modeling, artificial neural network and computational analysis

Arabian Journal of Chemistry, Journal Year: 2024, Volume and Issue: 17(9), P. 105863 - 105863

Published: June 12, 2024

Tumor stands as one of the principal contributors to global mortality. As research into tumor treatments advances, inhibitors emerge pivotal milestones in therapy. Among these inhibitors, Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, is critical owing its close association with cell proliferation and growth, which renders it therapeutic target. This work systematically explores relationship between chemical structures 36 piperidine carboxamide derivatives their efficacy inhibiting Karpas-299 activity by employing rigorous 3D-QSAR modeling approach. A robust Topomer CoMFA model was generated meticulously validated through ANN neural network analysis (q2 = 0.597, r2 0.939, F 84.401, N 4, SEE 0.268). Based on model, 60 new compounds desirable inhibitory activities were successfully designed. Combined Lipinski's rule ADMET criteria alongside molecular docking dynamics simulations, lead compound high good drug-likeness selected. Further computational analyses, encompassing free energy landscape binding calculations, provided compelling evidence stable conformation superior affinity target protein at active site, underscoring potential utility. In summary, this investigation offers valuable insights methodological guidance for advancing therapy underscores promise prospective ALK inhibitors.

Language: Английский

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In-silico design novel phenylsulfonyl furoxan and phenstatin derivatives as multi-target anti-cancer inhibitors based on 2D-QSAR, molecular docking, dynamics and ADMET approaches

Molecular Simulation, Journal Year: 2024, Volume and Issue: 50(6), P. 470 - 492

Published: March 13, 2024

A series of 31 hybrid phenylsulfonyl furoxan and phenstatin (1a-j, 2a-j, 3a-j, 4 5) derivatives, were computationally studied as potential anti-cancer inhibitors against four cell lines, i.e. A2780, MDA-MB-231, HCT-116 A549. In this work, the 2D-QSAR approach combining multiple linear regression (MLR) model, internal external cross-validation, showed a satisfactory quality factor: R2 = 0.85, 0.74, 0.82 0.75 for respectively. The binding affinity agents towards 4GL7, 6GUE, 1M17 4XL7 anti-tumoral targets was further evaluated using molecular docking dynamics simulations (0–200 ns). assessment parameters indicated formation satisfactorily stable complexes. addition, all considered data sets show that best affinity, including highest score, hydrogen bond energy amino acid steric interactions are well predicted best-selected developed model leveraged to design predict biological activity 12 new compounds (N1–N12) based on in-vivo inhibitor, namely, 3 h ligand formula: (4-((1-(2-((4-((3crylamidophenyl)amino)quinazolin-2-yl)thio)acetyl)piperidin-4-yl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide). Multitargeting scores they exhibit potent inhibition abilities proteins. Our in-silico outcomes would be combined with in-vitro studies provide perspective validation their activity. particular, ADMET predictions indicate designed ligands have demonstrated good drug-like profile can prospective candidates future therapies.

Language: Английский

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In silico Evaluation of Bisphosphonates Identifies Leading candidates for SARS-CoV-2 RdRp inhibition

Journal of Molecular Graphics and Modelling, Journal Year: 2025, Volume and Issue: 136, P. 108939 - 108939

Published: Jan. 7, 2025

Language: Английский

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Binding Selectivity of Inhibitors to BRD2 Uncovered by Molecular Docking and Molecular Dynamics Simulations

Advanced Theory and Simulations, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Abstract Bromodomain‐containing protein 2 (BRD2) plays a significant role in the development and progression of various diseases. Investigating binding selectivity two bromodomains BD1 BD2 BRD2 (BRD2‐BD1 BRD2‐BD2) with specific inhibitors can provide valuable insights for rational design novel therapeutic drugs. Thus, molecular dynamics (MD) simulations are employed to evaluate selective mechanisms three inhibitors, Spd16, BBC0403, SJ1461, toward BRD2‐BD1 BRD2‐BD2. Molecular Mechanics/Generalized Born Surface Area (MM‐GBSA) Solvation Interaction Energy (SIE) methods further analyze interaction modes compare free energies BRD2‐BD2 these inhibitors. Although exert different effects on internal structures BRD2‐BD2, their patterns similar. Phe372, Leu381, Tyr386, Cys425 play key roles between while Pro98, Leu108, Asn156, Ile162 critical residues Non‐polar interactions, particularly van der Waals serve as primary driving force behind The findings this study

Language: Английский

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Nanoparticle Formulations for Intracellular Delivery in Colorectal Cancer Therapy

AAPS PharmSciTech, Journal Year: 2025, Volume and Issue: 26(3)

Published: March 7, 2025

Language: Английский

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Identification of Potential PBP2a Inhibitors Against Methicillin‐Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy

Chemical Biology & Drug Design, Journal Year: 2025, Volume and Issue: 105(3)

Published: March 1, 2025

Methicillin-resistant Staphylococcus aureus (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented strategy combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric from an FDA-approved database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) two representative PBP2a structures. The combination SP one conformation showed highest efficacy in identifying compounds. optimized parameters then utilized screen drugs, 15 compounds shortlisted for cefazolin, ineffective cephalosporin MRSA. Through biological assays-checkerboard, time-kill assays, live/dead bacterial staining-we discovered four exhibited robust bactericidal activity (FICI < 0.5) compared both untreated control monotherapy cefazolin alone. Scanning electron microscopy (SEM) confirmed while alone did not cause visible damage MRSA cells, treatment markedly induced cell lysis. Additional MM-GBSA studies underscored strong binding affinity mitoxantrone site. These findings introduce approach potentially restores MRSA's susceptibility antibiotics.

Language: Английский

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Multispectral analysis and molecular simulation of quinoa protein-tannic acid interactions: Conformational changes and functional properties

Food Chemistry, Journal Year: 2025, Volume and Issue: 481, P. 143961 - 143961

Published: March 29, 2025

Language: Английский

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Discovery of a Potent and Selective Peptide Inhibitor with D-amino Acids Targeting the BRD4 ET Domain for Renal Cancer Therapy

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 294, P. 117767 - 117767

Published: May 15, 2025

Language: Английский

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Design and Development of New Generation ALK Inhibitors Driven by Structure–Activity Relationship Studies of 2,4‐Diarylaminopyrimidine Derivatives

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(21)

Published: June 1, 2025

Abstract Due to the oncogenic role of anaplastic lymphoma kinase (ALK) in various malignancies, particularly non‐small cell lung cancer (NSCLC), lymphoma, and neuroblastoma, mutations or rearrangements ALK frequently drive tumorigenesis progression. Consequently, development new‐generation inhibitors, therapeutic strategies targeting resistance mutations, has emerged as a critical focus drug research development. This study established robust Topomer CoMFA model, validated through both internal external assessments, Y‐randomization testing, validation with extreme learning machine (ELM) systematically analyze structure–activity relationships (SAR) series 52 derivatives, specifically designed 2,4‐diarylaminopyrimidines, which exhibit significant inhibitory activity. Based on optimal 24 novel compounds demonstrating ideal activity were successfully designed, three potential lead identified molecular docking. Subsequent investigations utilized DFT calculations, dynamics simulations, principal component analysis, binding free energy calculations elucidate modes mechanisms these compounds. Furthermore, ADMET predictions indicated promising pharmacological for These results offer substantial theoretical support targeted treatment ALK‐related tumors, while also laying groundwork future into inhibitors.

Language: Английский

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Conformational alterations and functional changes of pepsin induced by a novel food supplement tetrahydrocurcumin: Multispectral techniques and computer simulations

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 279, P. 135178 - 135178

Published: Aug. 29, 2024

Language: Английский

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