Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches

• Published in: PloS one Vol. 13; no. 6; p. e0199020
• Main Authors: Shinde, Ranajit Nivrutti, Kumar, G Siva, Eqbal, Shahbaz, Sobhia, M Elizabeth
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.06.2018; Public Library of Science (PLoS)
• Subjects: Allosteric properties; Allosteric Regulation - drug effects; Analysis; Annual reports; Binding sites; Bioinformatics; Catalytic Domain; Cluster Analysis; Computer Simulation; Databases, Pharmaceutical; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Drug Evaluation, Preclinical - methods; Drug therapy; Enzymes; Genetic aspects; Health aspects; Health education; Humans; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Inhibitors; Insulin; Ligands; Medical screening; Medicine and Health Sciences; Models, Molecular; Molecular chains; Molecular docking; Molecular dynamics; Molecular modelling; Nature conservation; Permeability; Pharmaceutical sciences; Pharmacology; Phosphatase; Phosphatases; Phosphorylation; Physical Sciences; Physiological aspects; Protein structure; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - drug effects; Protein-tyrosine-phosphatase; Proteins; Research and Analysis Methods; Residues; Screening; Signal transduction; Simulation; Therapeutic applications; Type 2 diabetes; Tyrosine; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0199020

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention. Interactions made by potent allosteric inhibitor in the presence of PTP1B were studied using Molecular Dynamics (MD). Computationally optimized models were used to build separate pharmacophore models of PTP1B and TCPTP, respectively. Based on the nature of interactions the target residues offered, a receptor based pharmacophore was developed. The pharmacophore considering conformational flexibility of the residues was used for the development of pharmacophore hypothesis to identify potentially active inhibitors by screening large compound databases. Two pharmacophore were successively used in the virtual screening protocol to identify potential selective and permeable inhibitors of PTP1B. Allosteric inhibition mechanism of these molecules was established using molecular docking and MD methods. The geometrical criteria values confirmed their ability to stabilize PTP1B in an open conformation. 23 molecules that were identified as potential inhibitors were screened for PTP1B inhibitory activity. After screening, 10 molecules which have good permeability values were identified as potential inhibitors of PTP1B. This study confirms that selective and permeable inhibitors can be identified by targeting allosteric site of PTP1B.