Modeling substrate efflux in human P-glycoprotein at the atomic level.

Human P-glycoprotein (hP-gp) is an ATP-binding cassette (ABC) exporter that actively extrudes a wide range of xenobiotics from the cell, thus limiting drug delivery and contributing to multidrug resistance (MDR) in cancers. Recent structural studies have provided insights into how hP-gp binds diverse compounds, but how they are translocated through the membrane remains poorly understood at the atomic level. In this work, we used steered molecular dynamics (SMD) simulations to investigate the molecular mechanism of how hP-gp expels structurally different compounds and which molecular features favor this efflux step.

Stiffness-tunable biomaterials provide a good extracellular matrix environment for axon growth and regeneration.

Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix-a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks.

Membrane-assisted tariquidar access and binding mechanisms of human ATP-binding cassette transporter P-glycoprotein.

The human multidrug transporter P-glycoprotein (P-gp) is physiologically essential and of key relevance to biomedicine. Recent structural studies have shed light on the mode of inhibition of the third-generation inhibitors for human P-gp, but the molecular mechanism by which these inhibitors enter the transmembrane sites remains poorly understood. In this study, we utilized all-atom molecular dynamics (MD) simulations to characterize human P-gp dynamics under a potent inhibitor, tariquidar, bound condition, as well as the atomic-level binding pathways in an explicit membrane/water environment.

2, 4, 5-Trideoxyhexopyranosides derivatives of diphyllin: Synthesis and anticancer activity.

Diphyllin and its natural derivatives were identified as potent vacuolar H -ATPase (V-ATPase) inhibitors. In this study, twelve 2, 4, 5-trideoxyhexopyranosides derivatives of diphyllin were synthesized. Most of these compounds showed potent abilities to inhibit the growth of HT-29, MCF-7, HepG2 cancer cells with IC values at submicromolar concentration.