P-glycoprotein
P-gp is a 170 kD protein containing two amino acid chains, each chain consists of six transmembrane domains (TMDs) and a nucleotidebinding ndomain (NBD).The flexible structure of P-gp is responsible for its translational and rotational motions during the efflux mechanism, which also includes simultaneous variation in the NBD distance, and is related to the entrance of a molecule suitable for efflux. One proposed structure of P-gp in open conformation is based on the crystal structure of mouse P-gp with the NBDs apart was used for mapping the binding site of the P-gp inhibitors. Conformational changes of P-gp start at the nucleotide-binding domains once a substrate or inhibitor enters the different binding domains. Function of a membrane transporter depends on the energy from ATP hydrolysis. It is suggested that binding of ATP to the NBD and dimerization of the NBD is a driving force for this function. The thickness of the membrane and its other properties such as phospholipid and cholesterol content have crucial roles in the ATPase activity of P-gp.
The presence of cholesterol is also essential for the activity of the P-gp pump. Molecular dynamic simulation analysis suggested that enhanced activity of P-gp for transporting substrates can be related to the cholesterol-rich domain of the membrane as accumulation of substrates occurs in this domain. Aromatic/hydrophobic interactions could be the key features in specification of the binding affinity for substrates/ modulators within the drug binding pocket of P-gp. Therefore, designing P-gp inhibitors that lack any interaction with CYP isoenzymes is an ideal perspective for future research.
References
1.Mollazadeh S, Sahebkar A, Hadizadeh F, Behravan J, Arabzadeh S. Life Sci. 2018;214:118–123. doi:10.1016/j.lfs.2018.10.048
The presence of cholesterol is also essential for the activity of the P-gp pump. Molecular dynamic simulation analysis suggested that enhanced activity of P-gp for transporting substrates can be related to the cholesterol-rich domain of the membrane as accumulation of substrates occurs in this domain. Aromatic/hydrophobic interactions could be the key features in specification of the binding affinity for substrates/ modulators within the drug binding pocket of P-gp. Therefore, designing P-gp inhibitors that lack any interaction with CYP isoenzymes is an ideal perspective for future research.
References
1.Mollazadeh S, Sahebkar A, Hadizadeh F, Behravan J, Arabzadeh S. Life Sci. 2018;214:118–123. doi:10.1016/j.lfs.2018.10.048
Membrane Transporter/Ion Channel
AMPK(58)
ASBT Transporter(6)
BCRP(10)
Beta Amyloid(69)
Carbonic Anhydrase(40)
Chloride Channel(34)
CRAC Channel(0)
CRM1(5)
Exportin-1(5)
FABP(6)
GAT(63)
GLUT(5)
Glutamate Transporter(1)
GlyT(13)
HCN Channel(5)
iGluR(52)
Monoamine Transporter(26)
Monocarboxylate Transporter(12)
MTP(1)
nAChR(5)
NADPH(35)
Na-K-ATPase(2)
NKCC(4)
NMDAR(65)
OCT(4)
Other Targets(13)
P2X Receptor(23)
P-glycoprotein(14)
Potassium Channel(0)
Proton Pump(38)
Sodium Channel(147)
TRP/TRPV Channel(115)
URAT1(1)
P-glycoprotein
-
Phellamurin
产品货号 : M29333
cas no: 52589-11-4
苯酚素以剂量依赖性方式抑制肠道P-糖蛋白,苯酚素与环孢素存在严重的相互作用,为保证环孢素的疗效,建议避免苯酚或黄柏与环孢素合用。 -
Alisol F 24-acetate
产品货号 : M29032
cas no: 443683-76-9
Alisol F 24-acetate 是从泽泻 (Alisma plantago-aquatica Linn) 中分离出来的天然产物。 Alisol F 24 Acetate 通过抑制 P-糖蛋白介导的药物流出来增强 MCF-7/DOX 细胞的化疗敏感性和细胞凋亡。 -
YS-370
产品货号 : M28486
cas no: 2470908-79-1
YS-370 是一种口服活性的 P-gp 抑制剂,对 CYP3A4 有中等程度的抑制作用。 YS-370可有效逆转紫杉醇和秋水仙碱的多药耐药性,并与紫杉醇联合显示出更强的抗肿瘤活性。 -
Encequidar mesylate
产品货号 : M26250
cas no: 849675-87-2
Encequidar mesylate 是一种竞争性 P-糖蛋白抑制剂。 -
Piperine (b)
产品货号 : M16782
cas no: 94-62-2
胡椒碱 (1-Piperoylpiperidine) 是一种生物碱,具有黑胡椒和荠菜的辛辣味。