Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent

Pang, Xu; Wang, Lin; Kyle, Dennis E.; Zhao, Ying; Wu, Song; Liu, Ailin; Du, Guanhua

doi:10.3390/molecules22081246

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…The ligand poses with top scoring are saved after a final energy-minimization step [ 38 ]. CDOCKER is the other important docking program in DS using a rigid receptor and CHARMmfield [ 39 ]. The interaction energy for each final pose of ligands with CHARMm energy was calculated, and the top scoring (most negative, thus favorable to binding) poses are retained.…”

Section: Methodsmentioning

confidence: 99%

Identification of Estrogen Receptor α Antagonists from Natural Products via In Vitro and In Silico Approaches

Pang

Wang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Estrogen receptor α (ERα) is a successful target for ER-positive breast cancer and also reported to be relevant in many other diseases. Selective estrogen receptor modulators (SERMs) make a good therapeutic effect in clinic. Because of the drug resistance and side effects of current SERMs, the discovery of new SERMs is given more and more attention. Virtual screening is a validated method to high effectively to identify novel bioactive small molecules. Ligand-based machine learning methods and structure-based molecular docking were first performed for identification of ERα antagonist from in-house natural product library. Naive Bayesian and recursive partitioning models with two kinds of descriptors were built and validated based on training set, test set, and external test set and then were utilized for distinction of active and inactive compounds. Totally, 162 compounds were predicted as ER antagonists and were further evaluated by molecular docking. According to docking score, we selected 8 representative compounds for both ERα competitor assay and luciferase reporter gene assay. Genistein, daidzein, phloretin, ellagic acid, ursolic acid, (−)-epigallocatechin-3-gallate, kaempferol, and naringenin exhibited different levels for antagonistic activity against ERα. These studies validated the feasibility of machine learning methods for predicting bioactivities of ligands and provided better insight into the natural products acting as estrogen receptor modulator, which are important lead compounds for future new drug design.

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Section: Methodsmentioning

confidence: 99%

Identification of Estrogen Receptor α Antagonists from Natural Products via In Vitro and In Silico Approaches

Pang

Wang

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…In the 1980s, the discovery by Tsuruo and colleagues [ 37 ] that verapamil can inhibit P-gp has marked a major milestone in this field of research. In previous papers, it was described that verapamil could bind the DBP and the NBP [ 34 , 38 , 39 ]. For these reasons, we focused our investigation on both DBP and NBP.…”

Section: Resultsmentioning

confidence: 99%

Phytol and Heptacosane Are Possible Tools to Overcome Multidrug Resistance in an In Vitro Model of Acute Myeloid Leukemia

et al. 2022

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Drug resistance is the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, and remains a major problem in cancer therapy. Resistance mechanisms are multifactorial and involve more strictly pharmacological factors, such as P-glycoprotein (P-gp) and biological factors such as inhibitor of apoptosis proteins (IAPs) and the nuclear factor-kappa B (NF-κB) pathway. Possible therapeutic strategies for the treatment of acute myeloid leukemia (AML) have increased in recent years; however, drug resistance remains a problem for most pa-tients. Phytol and heptacosane are the major compounds of Euphorbia intisy essential oil (EO) which were demonstrated to inhibit P-gp in a multidrug resistant in vitro model of AML. This study investigated the mechanism by which phytol and heptacosane improve P-gp-mediated drug transport. Phytol suppresses the P-gp expression via NF-κB inhibition and does not seem to act on the efflux system. Heptacosane acts as a substrate and potent P-gp inhibitor, demonstrating the ability to retain the substrate doxorubicin inside the cell and enhancing its cytotoxic effects. Our results suggest that these compounds act as non-toxic modulators of P-gp through different mechanisms and are able to revert P-gp-mediated drug resistance in tumor cells.

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“…Similarly, 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(3-(piperidin-1-yl)propan-1-one)dihydrochloride (DL0410), a novel synthetic dual AChE/ butyrylcholinesterase (BuChE) inhibitor for AD treatment, showed multitarget properties for AD treatment, such as improving cognitive deficits, enhancing synapse loss, inhibiting the activity of cholinesterase and reversing the plaque load caused by Aβ [98][99][100]. P-gp mediated DL0410 transport in Caco-2 and MDCK-MDR1 cells, suggesting that further efficacy and safety should be considered in drug-drug interactions in AD treatment [101].…”

Section: Abcb1mentioning

confidence: 99%

Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance

Jia¹,

Wang²,

Zhang³

et al. 2020

Aging and disease

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The neurovascular unit (NVU) plays an important role in maintaining the function of the central nervous system (CNS). Emerging evidence has indicated that the NVU changes function and molecules at the early stage of Alzheimer's disease (AD), which initiates multiple pathways of neurodegeneration. Cell types in the NVU have become attractive targets in the interventional treatment of AD. The NVU transportation system contains a variety of proteins involved in compound transport and neurotransmission. Brain transporters can be classified as members of the solute carrier (SLC) and ATP-binding cassette (ABC) families in the NVU. Moreover, the transporters can regulate both endogenous toxins, including amyloid-beta (Aβ) and xenobiotic homeostasis, in the brains of AD patients. Genome-wide association studies (GWAS) have identified some transporter gene variants as susceptibility loci for late-onset AD. Therefore, the present study summarizes changes in blood-brain barrier (BBB) permeability in AD, identifies the location of SLC and ABC transporters in the brain and focuses on major SLC and ABC transporters that contribute to AD pathology.

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Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent

Cited by 13 publications

References 27 publications

Identification of Estrogen Receptor α Antagonists from Natural Products via In Vitro and In Silico Approaches

Identification of Estrogen Receptor α Antagonists from Natural Products via In Vitro and In Silico Approaches

Phytol and Heptacosane Are Possible Tools to Overcome Multidrug Resistance in an In Vitro Model of Acute Myeloid Leukemia

Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance

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