Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors.
作者: Tagyedeen H Shoaib ; Nihal Abdelmoniem ; Rua M Mukhtar ; Amal Th Alqhtani ; Abdullah L Alalawi ; Razan Alawaji ; Mashael S Althubyani ; Shaimaa G A Mohamed ; Gamal A Mohamed ; Sabrin R M Ibrahim ; Hazem G A Hussein ; Abdulrahim A Alzain
The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.
Magnetic self-assembly of 3D multicellular microscaffolds: A biomimetic brain tumor-on-a-chip for drug delivery and selectivity testing.
In recent years, the need for highly predictive brain cancer models to test new anticancer compounds and experimental therapeutic approaches has significantly increased. Realistic in vitro brain tumor-on-a-chip platforms would allow a more accurate selection of valid candidate drugs and nanomedicines, therefore alleviating the economic and ethical issues of unsuccessful studies in vivo. Here, we present a multi-functional self-assembled brain tumor-on-a-chip model characterized by 3D glioma cultures interfaced both to nonmalignant brain cells of the peritumoral niche and to a 3D-real-scale blood-brain barrier (BBB) microfluidic system. This platform allowed us to screen multiple features, such as BBB crossing capabilities, apoptotic efficacy against GBM cells, and side effects on nonmalignant brain cells of a promising anticancer drug, nutlin-3a, which is fundamental for the treatment of brain cancer.
Interruption of p53-MDM2 Interaction by Nutlin-3a in Human Lymphoma Cell Models Initiates a Cell-Dependent Global Effect on Transcriptome and Proteome Level.
作者: Konstantina Psatha ; Laxmikanth Kollipara ; Elias Drakos ; Elena Deligianni ; Konstantinos Brintakis ; Eustratios Patsouris ; Albert Sickmann ; George Z Rassidakis ; Michalis Aivaliotis
In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 to proteasome-mediated degradation. In the present study, an integrating transcriptomics and proteomics analysis was employed to investigate the effect of p53 activation by a small-molecule MDM2-antagonist, nutlin-3a, on three lymphoma cell models following p53 activation. Our analysis revealed a system-wide nutlin-3a-associated effect in all examined lymphoma types, identifying in total of 4037 differentially affected proteins involved in a plethora of pathways, with significant heterogeneity among lymphomas. Our findings include known p53-targets and novel p53 activation effects, involving transcription, translation, or degradation of protein components of pathways, such as a decrease in key members of PI3K/mTOR pathway, heat-shock response, and glycolysis, and an increase in key members of oxidative phoshosphorylation, autophagy and mitochondrial translation. Combined inhibition of HSP90 or PI3K/mTOR pathway with nutlin-3a-mediated p53-activation enhanced the apoptotic effects suggesting a promising strategy against human lymphomas. Integrated omic profiling after p53 activation offered novel insights on the regulatory role specific proteins and pathways may have in lymphomagenesis.