Computational studies to explore inhibitors against the cyclin-dependent kinase 12/13 enzyme: an insilco pharmacophore modeling, molecular docking and dynamics approach DOI
Amar N. Ghosh, Prakash C. Jha, Anu Manhas

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 14

Published: Oct. 10, 2023

Cancer is enlisted among the deadliest disease all over world. The cyclin-dependent kinases 12 and 13 have been identified as cell cycle regulators. They conduct transcription co-transcriptional processes by phosphorylating C-terminal of RNA polymerase-II. Inhibition CDK12 selectively presents a novel strategy to treat triple-negative breast cancer, but dual inhibitors are still lacking. Here, we report screening natural product compound class against CDK12/13 enzyme employing various in silico methods. Complexes enzymes used form common feature pharmacophore models, whereas perform receptor-based modelling on CDK13 owing availability single PDB. On conducting representative pharmacophores, drug-like screened products were shortlisted for molecular docking studies. After calculations, candidates that showed crucial interaction with simulation Five docked selected dynamics simulations free energy calculations. Based cut-off criteria one hit was inhibitor. outcome concluded ID CNP0386383 possesses properties, displays binding pocket, shows stable dynamic behaviour higher than experimentally reported inhibitor both enzymes.Communicated Ramaswamy H. Sarma.

Language: Английский

Highly efficient synthesis of isoxazolones and pyrazolones using g-C3N4·OH nanocomposite with their in silico molecular docking, pharmacokinetics and simulation studies DOI Creative Commons
Shivani Soni, Sunita Teli, Pankaj Teli

et al.

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

Published: Aug. 18, 2024

An environmentally friendly, versatile multicomponent reaction for synthesizing isoxazol-5-one and pyrazol-3-one derivatives has been developed, utilizing a freshly prepared g-C

Language: Английский

Citations

5
Anticancer efficacy of thiazole-naphthyl derivatives targeting DNA: Synthesis, crystal structure, density functional theory, molecular docking, and molecular dynamics studies DOI

Abhishek Aher,

Pradip Bera, Paula Brandão

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 140039 - 140039

Published: Jan. 1, 2025

Language: Английский

Citations

0
Insights into curcumin’s anticancer activity in pancreatic ductal adenocarcinoma: Experimental and computational evidence targeting HRAS, CCND1, EGFR and AKT1 DOI
Jun‐Feng Cao, Xiao Zhang,

Qingjie Xia

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 157, P. 108264 - 108264

Published: Feb. 8, 2025

Language: Английский

Citations

0
Binding Mechanism of Inhibitors to CDK6 Deciphered by Multiple Independent Molecular Dynamics Simulations and Free Energy Predictions DOI Creative Commons
Lifei Wang, Yan Wang,

Lulu Zhang

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(5), P. 979 - 979

Published: Feb. 20, 2025

Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations four separate replicates and computations binding free energies are carried out to decipher the mechanisms three inhibitors, LQQ, 6ZV, 0RS, CDK6. The dynamic analyses indicate that presence inhibitors influences conformational alterations, motion modes, internal Binding computed using mechanics generalized Born surface area (MM-GBSA) approach with GB models demonstrate hydrophobic interactions play essential roles inhibitor-CDK6 binding. residue-based energy decomposition verify side chains residues I19, K29, M54, P55, F98, H100, L152 significantly contribute binding, revealing critical interaction sites for information revealed study can provide theoretical aids development potent targeting CDK family.

Language: Английский

Citations

0
Identification of Diagnostic Biomarkers and Therapeutic Targets for Abdominal Aortic Aneurysms Based on Disulfidptosis Mechanism DOI Creative Commons

Ronggui Chen,

Junzhu Shi, Yipeng Zhang

et al.

Current Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach DOI Creative Commons

Nisarg Rana,

Dhaval Patel,

Meet Parmar

et al.

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

Published: Oct. 23, 2023

Cancer has been viewed as one of the deadliest diseases worldwide. Among various types cancer, breast cancer is most common type in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) a promising druggable target and overexpressed cancerous cells, like, cancer. We conducted structure-based modeling on allosteric site enzyme. Targeting avoids problem drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per literature, average superimposed simulated structures revealed similar protein conformational change αE'-βf' loop, causing its displacement away from site. MM-PBSA tight binding six compounds with pocket. effect inhibitors interacting causes decrease energy J49 (active-site inhibitor), suggesting binding. PCA FEL analysis significance docked behaviour complexes. outcome can contribute to development potential natural products drug-like properties inhibit MTHFD2

Language: Английский

Citations

10
Targeting the Cyclin-Dependent Kinase Family in Anticancer Drug Discovery: From Computational to Experimental Studies DOI Creative Commons

Priyanka Solanki,

Shubhangi Sarwadia,

Mohd Athar

et al.

Chemical Physics Impact, Journal Year: 2024, Volume and Issue: 9, P. 100768 - 100768

Published: Nov. 2, 2024

Language: Английский

Citations

1
Insights into the selective mechanism of PDE2/9a inhibitors from silico aspects DOI
Pengfei Song, Shizun Wang,

Rongye Han

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 18

Published: March 25, 2024

The selective design of competitive enzyme inhibitors is an extremely difficult task but necessary work for certain types systems, such as the phosphodiesterase (PDE) system addressed in this article. In PDE family, PDE2A and PDE9 respectively target central nervous heart failure, share many conserved amino acids at their binding sites. Therefore, gaining a deep understanding mechanisms PDE2A/9A crucial designing highly drugs. study, various computer-aided drug (CADD) methods, including molecular docking, dynamics simulations (MD), free energy calculations, are employed to explore PDE2A/9A. Overall, our research results indicate strategy PDE2A, which involves incorporating hydrophobic or aromatic moieties into structure better accommodate pocket PDE2A. Additionally, it recommended introduce functional groups capable forming connections with residues, Phe830 Gln812 Ala452 Tyr424 PDE9A, enhance selectivity targeting This achievement anticipated pave way development innovative small molecules

Language: Английский

Citations

0
3-Methyladenine potentiates paclitaxel-induced apoptosis and phosphorylation of cyclin-dependent kinase 1 at thr161 in nasopharyngeal carcinoma cell DOI Open Access

XIAOQI WU,

YECHUAN HE,

Yeqin Yuan

et al.

Biocell, Journal Year: 2024, Volume and Issue: 48(5), P. 861 - 872

Published: Jan. 1, 2024

Background: Nasopharyngeal carcinoma (NPC) exhibits a significant prevalence in the southern regions of China, and paclitaxel (PTX) is frequently employed as medication for managing advanced NPC.However, drug resistance typically accompanied by poor prognosis.Exploring synergistic potential combining multiple chemotherapeutic agents may represent promising avenue optimizing treatment efficacy.Methods: This study investigated whether 3-Methyladenine (3-MA) could potentiated effect PTX its molecular mechanism.Samples were divided into following categories: Negative control (NC) with solvent dimethyl sulfoxide (DMSO, 0.5% v/v), (400 nM), 3-MA (4 mM), nM) + mM).The viability NPC cells was assessed using both cell counting kit-8 (CCK-8) assay colony formation assay.Microscopic observation performed to identify morphological changes.Flow cytometry used assess cycle status, mitochondrial membrane (MMP), apoptotic cells.Western blotting conducted quantify protein expression.Results: enhanced PTX-specific inhibition proliferation.PTX, either alone or combination 3-MA, caused halt at G 2 /M phase majority cells, induced higher rate death compared alone.Western results revealed heightened activation cyclin-dependent kinase 1 (CDK1), key molecule shifting from mitotic arrest apoptosis, led reduction Myeloid Cell Leukemia (MCL-1) expression an increase Poly (ADP-ribose) polymerase (PARP) cleavage.Conclusion: The concurrent administration effectively enhances PTX's inhibitory impact on activates apoptosis signal regulated CDK1.

Language: Английский

Citations

0
Screening of synthesized perimidine compounds for the assessment of antimicrobial potential: in-vitro and in-silico molecular docking and molecular dynamics simulation studies DOI Creative Commons
Nusrat Sahiba, Deepkumar Joshi, Lokesh Kumar Agarwal

et al.

Discover Chemistry., Journal Year: 2024, Volume and Issue: 1(1)

Published: Oct. 9, 2024

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack efficacy drugs, low drug discovery rate. Considering the importance N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction 1,8-diaminonaphthalene aryl aldehydes. Further, perimidines were screened potent agents in-vitro, in-silico, ADME MD simulation studies. All 22 studied against two-gram +ve (E. coli P. aeruginosa), −ve (S. aureus B. subtilis), two fungal (A. niger S. cerevisiae) strains using ciprofloxacin fluconazole reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, 3m most 3(a–d), 3(g–i), 3s active subtilis compared standard. Furthermore, molecular docking studies performed Dihydrofolate reductase (PDB Id: 3SRW) from aureus, DNA gyrase 4DUH) E. coli, ERG11 gene 4LXJ). Compounds 3f, 3f/3m, 3o found bind efficiently with highest binding energy − 10.6, 9.6, 11.3kcal/mol depicting potential inhibitor 3SRW, 4DUH, 4LXJ receptor protein, respectively. drug-likeness properties SwissADME program. To further validate these findings, dynamics simulations conducted evaluate their stability. From studies, it was observed all shortlisted displayed stable within site selected proteins.

Language: Английский

Citations

0