Identification of Potential Inhibitors of TGFβR1 for the treatment of Cancer through Structure‐based virtual screening and Molecular dynamics simulations DOI
Saumya Rastogi, Shashank Shekher Mishra, Lakhveer Singh

et al.

Chemistry & Biodiversity, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 21, 2024

Abstract Globally, cancer is one of the leading causes death. Resistance to conventional medications, such as chemotherapy and radiation, continues be a significant challenge in treatment despite availability numerous medicines. Therefore, highest priority hunt for new therapeutic agents. Transforming growth factor‐beta pivotal regulatory cytokine that exerts influence over cellular processes, particularly emphasizing its role facilitating modulating cell proliferation. TGF‐β receptor 1, identified most promising active site signaling, potent drug target has garnered wide attention developing anticancer The present investigation investigates potential natural products TGFβR1 inhibitors. SB431542 complexed protein model was used screen product database obtain compound with high binding potential. NPC247629 emerged best‐scored among all screened compounds, demonstrating affinity towards regarding docking score −17.54 kcal/mol. all‐atoms MD simulation study indicated proposed hits are retained inside dynamic states. Additionally, principal component free energy landscape analysis were performed explore mechanism top‐hit products. best‐screened hits, NPC60735, have excellent hold massive inhibition, paving way future investigations treatment.

Language: Английский

New theobromine derivative as apoptotic anti-triple-negative breast cancer targeting EGFR protein: CADD story DOI
Ibrahim H. Eissa, Reda G. Yousef, Hazem Elkady

et al.

Journal of Molecular Structure, Journal Year: 2023, Volume and Issue: 1294, P. 136336 - 136336

Published: Aug. 8, 2023

Language: Английский

Citations

30
New Theobromine Derivatives Inhibiting VEGFR-2: Design, Synthesis, Antiproliferative, Docking and Molecular Dynamics Simulations DOI

Hazem A. Mahdy,

Hazem Elkady, Mohammed S. Taghour

et al.

Future Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(14), P. 1233 - 1250

Published: July 1, 2023

Background: VEGFR-2 is one of the most effective targets in cancer treatment. Aim: The design and semi-synthesis new theobromine derivatives as potential inhibitors. Methods: In vitro silico evaluation synthesized compounds. Results: Compound 5b demonstrated excellent antiproliferative inhibitory effects with significant apoptotic activity. It modulated immune response by increasing IL-2 reducing TNF-α levels. Docking molecular dynamics simulations revealed compound’s binding affinity VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion toxicity studies indicated high compound for drug development. Conclusion: could be a promising anticancer agent targeting

Language: Английский

Citations

17
Anti-virulence potential of patuletin, a natural flavone, against Staphylococcus aureus: In vitro and In silico investigations DOI Creative Commons
Ahmed M. Metwaly, Moustafa M. Saleh, Bshra A. Alsfouk

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(2), P. e24075 - e24075

Published: Jan. 1, 2024

is a highly prevalent and aggressive human pathogen causing wide range of infections. This study aimed to explore the potential Patuletin, rare natural flavone, as an anti-virulence agent against

Language: Английский

Citations

7
Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer DOI Creative Commons
Nesma Abdelaal, Mohamed A. Ragheb, Hamdi M. Hassaneen

et al.

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

Published: Nov. 4, 2024

Language: Английский

Citations

7
Integrated in silico and in vitro exploration of the anti-VEGFR-2 activities of a semisynthetic xanthine alkaloid inhibiting breast cancer DOI Creative Commons
Eslam B. Elkaeed, Hazem Elkady, Ahmed M. Khattab

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0316146 - e0316146

Published: Jan. 27, 2025

This study presents T-1-NBAB , a new compound derived from the natural xanthine alkaloid theobromine, aimed at inhibiting VEGFR-2, crucial protein in angiogenesis. ’s potential to interacts with and inhibit VEGFR-2 was indicated using silico techniques like molecular docking, MD simulations, MM-GBSA, PLIP, essential dynamics, bi-dimensional projection experiments. DFT experiments utilized also structural electrostatic properties of . Computational analysis performed predict ADME-Tox profiles After semisynthesis, vitro results showed that effectively inhibits an IC 50 0.115 μM, compared sorafenib’s 0.0591 μM. In tests demonstrated significant activity against breast cancer cell lines MCF7 T47D, values 16.88 μM 61.17 respectively, high selectivity. Importantly, induced early late apoptosis cells, indicating its as strong anticancer agent. Additionally, reduced migration healing abilities suggesting it could be promising anti-angiogenic Overall, these findings suggest is lead for further research treatment cancer.

Language: Английский

Citations

0
A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies DOI Creative Commons
Ibrahim H. Eissa, Reda G. Yousef, Hazem Elkady

et al.

ChemistryOpen, Journal Year: 2023, Volume and Issue: 12(10)

Published: Oct. 1, 2023

Abstract A computer‐assisted drug design (CADD) approach was utilized to a new acetamido‐ N ‐(para‐fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, ( T‐1‐APFPB ), following pharmacophoric features VEGFR‐2 inhibitors. The stability and reactivity T‐1‐AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed ’s potential bind with inhibit VEGFR‐2. precise binding against optimal energy further confirmed several molecular dynamics (MD) simulations, PLIP, MM‐GBSA, PCA studies. Then, (4‐(2‐(3,7‐Dimethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1 H ‐purin‐1‐yl)acetamido)‐ ‐(4‐fluorophenyl)benzamide) semi‐synthesized in vitro assays its an IC 50 value 69 nM (sorafenib's 56 nM) growth HepG2 MCF‐7 cancer cell lines values 2.24±0.02 3.26±0.02 μM, respectively. Moreover, displayed very high selectivity indices normal Vero lines. Furthermore, induced early (from 0.72 19.12) late 0.13 6.37) apoptosis In conclusion, combined computational experimental approaches demonstrated efficacy safety providing it as promising lead inhibitor for development aiming at therapy.

Language: Английский

Citations

9
Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations DOI
Mohammed A. Dahab,

Hazem A. Mahdy,

Hazem Elkady

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(8), P. 4214 - 4233

Published: June 1, 2023

Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic causing the development of tumors. Sothat, inhibition VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as inhibitors subjected to vitro testing for their ability block activation. Furthermore, antiproliferative effects these evaluated. Compound 7 g exhibited most potent anti-VEGFR-2 activity, with an IC50 value 0.072 µM, demonstrated excellent dose-dependent inhibitory activity against both MCF-7 HepG2 cells values 19.35 27.89 respectively. Notably, compound high selectivity indices 2.6 1.8 cells, induced G2/M phase cycle arrest, promoted apoptosis, immunomodulation downregulating TNF-α upregulating IL-2 levels cells. The molecular docking analysis revealed that could bind effectively active site VEGFR-2, dynamic simulations confirmed stability VEGFR-2/compound complex. ADME toxicity profiling indicated potential suitability compounds drug candidates. summary, hold promise a inhibitor.Communicated Ramaswamy H. Sarma

Language: Английский

Citations

8
New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies DOI Creative Commons
Ibrahim H. Eissa, Reda G. Yousef, Eslam B. Elkaeed

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(14), P. 15861 - 15881

Published: March 27, 2024

Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics existing EGFR inhibitors as foundation. Method: began natural alkaloid theobromine developed new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first evaluate its anticipated safety general drug-likeness. Deep density functional theory (DFT) computations initially performed validate three-dimensional (3D) structure reactivity T-1-PMPA. Molecular docking against proteins investigate T-1-PMPA's binding affinity inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along MM-GPSA, PLIP, principal component analysis trajectories (PCAT) experiments employed verify Afterward, T-1-PMPA semisynthesized proposed in silico findings through several vitro examinations. Results: DFT studies indicated using electrostatic potential, global reactive indices, total states. docking, MD simulations, ED suggested protein. predicted In demonstrated that effectively inhibited EGFRWT EGFR790m, IC50 values 86 561 nM, respectively, compared Erlotinib (31 456 nM). also showed significant suppression proliferation HepG2 MCF7 malignant cell lines, 3.51 4.13 μM, respectively. selectivity indices two cancer lines overall Flow cytometry confirmed effects increasing percentage apoptosis 42% 31, 3% Erlotinib-treated control cells, qRT-PCR further supported revealing increases levels Casp3 Casp9. Additionally, controlled TNFα IL2 74 50%, comparing Erlotinib's (84 74%), Conclusion: conclusion, our study's suggest potential promising anticancer lead compound targeting EGFR.

Language: Английский

Citations

2
Visible-light promoted catalyst-free (VLCF) multi-component synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids: evaluation of in vitro anticancer activity, molecular docking, MD simulation and DFT studies DOI
Safia Iqbal,

Farhanaz,

Roohi Roohi

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(6), P. 3145 - 3165

Published: May 25, 2023

A new and highly efficient visible-light-promoted catalyst free (VLCF) strategy for neat clean synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids (6a–d) has been introduced. We have performed visible-light triggered 1,3-Dipolar cycloaddition reaction maleimide (5a–d) with azomethine ylide generated in situ derived from tryptanthrin (3) L-proline (4) to obtain desired products good excellent yield. Authentication characterization product was done using various spectroscopic techniques such as IR, 1H NMR, 13C Mass spectrometry single crystal XRD analysis. To explain the spontaneity, stability, reactivity well possible mode interaction a quantum chemical investigation depicted through DFT studies. The synthesized compound 6a also evaluated anti-proliferative activity against panel five cancer cell lines (MCF-7, MDA-MB-231, HeLa, PC-3 Ishikawa) normal human embryonic kidney (HEK-293) line by MTT assay. Compound showed very vitro (IC50 = 6.58–17.98 μM) four no cytotoxicity HEK-293. In order evaluate anticancer potential compounds 6a-d, molecular docking wild type mutant EGFR. results suggest that all occupied active site both enzymes, strong binding energy (−10.2 −11.5 kcal/mol). These confirmed dynamics simulation evaluating root mean square deviation (RMSD) fluctuation (RMSF), along principal component analysis (PCA).Communicated Ramaswamy H. Sarma

Language: Английский

Citations

6
Design, synthesis, biological evaluation and computational studies of 4-Aminopiperidine-3, 4-dihyroquinazoline-2-uracil derivatives as promising antidiabetic agents DOI Creative Commons

Ladan Baziar,

Leila Emami, Zahra Rezaei

et al.

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

Published: Nov. 3, 2024

A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors antidiabetic agents. Chemical structure all new compounds confirmed by different spectroscopic methods. The evaluated using a MAK 203 kit in comparison with Sitagliptin. biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety 6-bromo quinazoline ring had promising inhibitory activity IC50 = 9.25 ± 0.57 µM. toxicity test safety profile them. Kinetic studies showed exhibited competitive-type inhibition Ki value 12.01 Computational approach supported the rationality our design strategy, represented appropriate binding interactions active sites target. MD simulation outputs validated stability ligand at site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, theoretical IR spectrum was employed to study reactivity descriptors 9a most least respectively. Based DFT study, softer and, result, more reactive than 9a. Taken together, results potential candidates for developing some managing type 2 diabetes.

Language: Английский

Citations

1