In silico screening of natural products as uPAR inhibitors via multiple structure-based docking and molecular dynamics simulations DOI
Song Xie,

Guiqian Yang,

Juhong Wu

и другие.

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер unknown, С. 1 - 12

Опубликована: Дек. 18, 2023

Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. metastasis is critical determinant lethality and treatment resistance cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as target for anticancer antimetastatic therapies. In this work, we aimed identify uPAR inhibitors by structural dynamics-based virtual screenings against natural product library four representative apo-uPAR models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen (NP1-NP15) were initially identified through docking, consensus scoring, visual inspection. Subsequently, employed MD-based mechanics-generalized Born surface area (MM-GBSA) calculations evaluate their binding affinities uPAR. Structural analyses further indicated that all top 6 compounds exhibited stable interacted with residues in interface between its endogenous ligand uPA, suggesting interrupting uPAR-uPA interaction. We finally predicted ADMET properties these compounds. products NP5, NP12, NP14 better than previously discovered us proven be potentially orally active humans. This work offers may contribute development novel effective therapeutics.Communicated Ramaswamy H. Sarma.

Язык: Английский

Oral administration of proniosomal glibenclamide formulation protects testicular tissue from hyperglycemia fluctuations and ROS via Nrf2/HO-1 pathway DOI Creative Commons
Nouf M. Alyami,

Zainab A. Alnakhli,

Noura M. Alshiban

и другие.

Heliyon, Год журнала: 2024, Номер 10(10), С. e31283 - e31283

Опубликована: Май 1, 2024

Type 2 diabetes causes high blood sugar due to insulin malfunction and is linked male infertility. Using proniosomes can enhance the effectiveness of Glibenclamide, a medication that stimulates secretion. In our study, rats with were treated GLB or without proniosomal for 14 days. Proniosomal formulations maintained glucose levels prevented weight loss showed normal testicular tissue.GLB-proniosomal reduces ROS caused by T2DM through Nrf2, HO-1 pathway increases CAT, SOD, GSH production in response uptake. The reference treatments CAT SOD significant enzymatic elevation compared positive negative control. significantly correlated Gpx4 expression P = 0.0169 r 0.98; similarly, activity also correlation between average (r 0.99 0.0037). Intestinally, analysis revealed only proniosomal-GLB samples are elevated from control, value 0.0210. data was more effective than pure GLB, confirmed higher Nrf2 (2.050 folds), (2.148 GPx4 (1.9 folds) transcript relative control less sample diversity samples, indicating stabilized blood.Administering formulation has effectively restored function sperm diabetic regulating upregulating anti-ROS These findings may lead better patients who have infertility issues.

Язык: Английский

Процитировано

2
Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation DOI

Song Xie,

Yang Zhou, Hao Zhu

и другие.

Molecular Diversity, Год журнала: 2024, Номер unknown

Опубликована: Июнь 27, 2024

Язык: Английский

Процитировано

1
Targeted imaging of uPAR expression in vivo with cyclic AE105 variants DOI Creative Commons
Julie Maja Leth, Estella A. Newcombe, Anne Louise Grønnemose

и другие.

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Окт. 11, 2023

A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and severity diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans stratify patients for targeted treatment. To date, only probe targeting uPAR that has reached clinical phase-II testing relies high-affinity 9-mer peptide (AE105), several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence have validated its utility specificity in vivo. While our previous focused applying various reporter groups, current study aims improve uPAR-targeting properties AE105. We successfully stabilized small core AE105 constraining conformational landscape disulfide-mediated cyclization. Importantly, this modification mitigated penalty uPAR-affinity typically observed after conjugation macrocyclic chelators. Cyclization did not impair tumor efficiency vivo assessed PET trend towards increased tracer uptake was observed. In future studies, we predict knowledge will aid development new fluorescent derivatives view optical assist precision guided cancer surgery.

Язык: Английский

Процитировано

1
In silico screening of natural products as uPAR inhibitors via multiple structure-based docking and molecular dynamics simulations DOI
Song Xie,

Guiqian Yang,

Juhong Wu

и другие.

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер unknown, С. 1 - 12

Опубликована: Дек. 18, 2023

Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. metastasis is critical determinant lethality and treatment resistance cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as target for anticancer antimetastatic therapies. In this work, we aimed identify uPAR inhibitors by structural dynamics-based virtual screenings against natural product library four representative apo-uPAR models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen (NP1-NP15) were initially identified through docking, consensus scoring, visual inspection. Subsequently, employed MD-based mechanics-generalized Born surface area (MM-GBSA) calculations evaluate their binding affinities uPAR. Structural analyses further indicated that all top 6 compounds exhibited stable interacted with residues in interface between its endogenous ligand uPA, suggesting interrupting uPAR-uPA interaction. We finally predicted ADMET properties these compounds. products NP5, NP12, NP14 better than previously discovered us proven be potentially orally active humans. This work offers may contribute development novel effective therapeutics.Communicated Ramaswamy H. Sarma.

Язык: Английский

Процитировано

1