title: Protein tyrosine phosphatase 1B inhibitory activity of alkaloids from Rhizoma Coptidis and their molecular docking studies.
abstract: BACKGROUND
  Rhizoma Coptidis (the rhizome of Coptis chinensis Franch) has commonly been used for treatment of diabetes mellitus in traditional Chinese medicine due to its blood sugar-lowering properties and therapeutic benefits which highly related to the alkaloids therein. However, a limited number of studies focused on the Coptis alkaloids other than berberine.
  
  
  METHODS
  In the present study, we investigated the anti-diabetic potential of Coptis alkaloids, including berberine (1), epiberberine (2), magnoflorine (3), and coptisine (4), by evaluating the ability of these compounds to inhibit protein tyrosine phosphatase 1B (PTP1B), and ONOO(-)-mediated protein tyrosine nitration. We scrutinized the potentials of Coptis alkaloids as PTP1B inhibitors via enzyme kinetics and molecular docking simulation.
  
  
  RESULTS
  The Coptis alkaloids 1-4 exhibited remarkable inhibitory activities against PTP1B with the IC50 values of 16.43, 24.19, 28.14, and 51.04 μM, respectively, when compared to the positive control ursolic acid. These alkaloids also suppressed ONOO(-)-mediated tyrosine nitration effectively in a dose dependent manner. In addition, our kinetic study using the Lineweaver-Burk and Dixon plots revealed that 1 and 2 showed a mixed-type inhibition against PTP1B, while 3 and 4 noncompetitively inhibited PTP1B. Moreover, molecular docking simulation of these compounds demonstrated negative binding energies (Autodock 4.0=-6.7 to -7.8 kcal/mol; Fred 2.0=-59.4 to -68.2 kcal/mol) and a high proximity to PTP1B residues, including Phe182 and Asp181 in the WPD loop, Cys215 in the active sites and Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221 and Gln262 in the pocket site, indicating a higher affinity and tighter binding capacity of these alkaloids for the active site of the enzyme.
  
  
  CONCLUSIONS
  Our results clearly indicate the promising anti-diabetic potential of Coptis alkaloids as inhibitors on PTP1B as well as suppressors of ONOO(-)-mediated protein tyrosine nitration, and thus hold promise as therapeutic agents for the treatment of diabetes and related disease.
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea. Electronic address: choijs@pknu.ac.kr.
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Md Yousof
authors.initials: MY
authors.lastname: Ali
authors.affiliation: Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 561-756, Republic of Korea. Electronic address: jungha@jbnu.ac.kr.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Jung
authors.affiliation: Korean BioInformation Center (KOBIC), Daejeon 305-806, Republic of Korea.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Angiogenesis & Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Ran Joo
authors.initials: RJ
authors.lastname: Choi
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Eon Ji
authors.initials: EJ
authors.lastname: Kim
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D039323:Coptis; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology; D062105:Molecular Docking Simulation; D030421:Peroxynitrous Acid / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027343:Rhizome / Q000737:chemistry; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000470:Alkaloids; D007004:Hypoglycemic Agents; D010936:Plant Extracts; D030421:Peroxynitrous Acid; D014443:Tyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Alkaloids; Enzyme kinetics; Molecular docking; Protein tyrosine phosphatase 1B; Rhizoma Coptidis