Combined Ligand‐ and Receptor‐Based Virtual Screening Methodology to Identify Structurally Diverse Protein Tyrosine Phosphatase 1B Inhibitors

• Published in: ChemMedChem Vol. 13; no. 18; pp. 1939 - 1948
• Main Authors: Gimeno, Aleix, Ardid‐Ruiz, Andrea, Ojeda‐Montes, María José, Tomás‐Hernández, Sarah, Cereto‐Massagué, Adrià, Beltrán‐Debón, Raúl, Mulero, Miquel, Valls, Cristina, Aragonès, Gerard, Suárez, Manuel, Pujadas, Gerard, Garcia‐Vallvé, Santiago
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 19.09.2018
• Subjects: Bioavailability; Biological activity; Chemical fingerprinting; Diabetes mellitus; Dose-Response Relationship, Drug; Drug development; Drug Evaluation, Preclinical; Endocytosis; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitors; Lead compounds; Ligands; Models, Molecular; Molecular Structure; obesity; Organic chemistry; Phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein-tyrosine-phosphatase; Proteins; Screening; Structure-Activity Relationship; type 2 diabetes mellitus; Tyrosine; virtual screening; Workflow; type 2 diabetes mellitus; inhibitors; virtual screening; protein tyrosine phosphatase; obesity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800267

Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for diabetes and obesity. However, the design of PTP1B inhibitors that combine potency and bioavailability is a great challenge, and new leads are needed to circumvent this problem. Virtual screening (VS) workflows can be used to find new PTP1B inhibitors with little chemical similarity to existing inhibitors. Unfortunately, previous VS workflows for the identification of PTP1B inhibitors have several limitations, such as a small number of experimentally tested compounds and the low bioactivity of those compounds. We developed a VS workflow capable of identifying 15 structurally diverse PTP1B inhibitors from 20 compounds, the bioactivity of which was tested in vitro. Moreover, we identified two PTP1B inhibitors with the highest bioactivity reported by any VS campaign (i.e., IC50 values of 1.4 and 2.1 μm), which could be used as new lead compounds. Broadening the horizon: We developed a virtual screening (VS) workflow that consists of a combination of ligand‐ and receptor‐based methods. With this approach we were able to identify 15 structurally diverse protein tyrosine phosphatase 1B (PTP1B) inhibitors, two of them with IC50 values in the 1–10 μm range. This new VS method has proven useful in broadening the scope of the types of compounds potentially suitable as leads for treating diabetes and obesity.