Molecular Dynamics Approach to Probe the Allosteric Inhibition of PTP1B by Chlorogenic and Cichoric Acid

• Published in: Journal of chemical information and modeling 2012-08, Vol.52 (8), p.2004-2012
• Main Authors: Baskaran, Sarath Kumar, Goswami, Nabajyoti, Selvaraj, Sudhagar, Muthusamy, Velusamy Shanmuganathan, Lakshmi, Baddireddi Subhadra
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Allosteric Site - drug effects; Biological and medical sciences; Caffeic Acids - chemistry; Caffeic Acids - metabolism; Caffeic Acids - pharmacology; Cell physiology; Chlorogenic Acid - chemistry; Chlorogenic Acid - metabolism; Chlorogenic Acid - pharmacology; Diabetes; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; General pharmacology; Humans; Interactions. Associations; Intermolecular phenomena; Intervention; Medical sciences; Molecular and cellular biology; Molecular biophysics; Molecular Docking Simulation; Molecular Dynamics Simulation; Obesity; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Proteins; Signal transduction; Simulation; Succinates - chemistry; Succinates - metabolism; Succinates - pharmacology
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci200581g

Protein tyrosine phosphatase 1B (PTP1B), a major negative regulator of the insulin and leptin signaling pathway, is a potential target for therapeutic intervention against diabetes and obesity. The recent discovery of an allosteric site in PTP1B has created an alternate strategy in the development of PTP1B targeted therapy. The current study investigates the molecular interactions between the allosteric site of PTP1B with two caffeoyl derivatives, chlorogenic acid (CGA) and cichoric acid (CHA), using computational strategies. Molecular docking analysis with CGA and CHA at the allosteric site of PTP1B were performed and the resulting protein–ligand complexes used for molecular dynamics simulation studies for a time scale of 10 ns. Results show stable binding of CGA and CHA at the allosteric site of PTP1B. The flexibility of the WPD loop was observed to be constrained by CGA and CHA in the open (inactive), providing molecular mechanism of allosteric inhibition. The allosteric inhibition of CGA and CHA of PTP1B was shown to be favorable due to no restriction by the α-7 helix in the binding of CGA and CHA at the allosteric binding site. In conclusion, our results exhibit an inhibitory pattern of CGA and CHA against PTP1B through potent binding at the allosteric site.