Dimeric phenalenones from Talaromyces sp. (IQ-313) inhibit hPTP1B1-400: Insights into mechanistic kinetics from in vitro and in silico studies

• Published in: Bioorganic chemistry 2020-08, Vol.101, p.103893-103893, Article 103893
• Main Authors: Jiménez-Arreola, Brenda S., Aguilar-Ramírez, Enrique, Cano-Sánchez, Patricia, Morales-Jiménez, Jesús, González-Andrade, Martín, Medina-Franco, José L., Rivera-Chávez, José
• Format: Article
• Language: English
• Subjects: Allosteric modulators/inhibitors; Dimeric phenalenones; Duclauxin; Homology modeling; hPTP1B1-400; Talaromyces sp
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103893

[Display omitted] •The biochemical characterization of a full-length human PTP1B (hPTP1B1-400).•Four dimeric phenalenones were isolated from an anthill associated Talaromyces sp.•Dimeric phenalenones and ursolic acid are allosteric inhibitors of hPTP1B1-400.•A homology model for hPTP1B1-400 was built to perform in silico studies.•The use of truncated models of PTP1B lead to the loss of valuable information. A critical biological event that contributes to the appearance and progress of cancer and diabetes is the reversible phosphorylation of proteins, a process controlled by protein tyrosine-kinases (PTKs) and protein tyrosine-phosphatases (PTPs). Within the PTPs, PTP1B has gained significant interest since it is a validated target in drug discovery. Indeed, several PTP1B inhibitors have been developed, from both, synthesis and natural products. However, none have been approved by the FDA, due to their poor selectivity and/or pharmacokinetic properties. One of the most significant challenges to the discovery of PTP1B inhibitors (in vitro or in silico) is the use of truncated structures (PTP1B1-300), missing valuable information about the mechanisms of inhibition, and selectivity of ligands. The present study describes the biochemical characterization of a full-length PTP1B (hPTP1B1-400), as well as the description of phenalenones 1–4 and ursolic acid (5) as allosteric modulators. Compounds 1–5 showed inhibitory potential on hPTP1B1-400, with IC50 values ranging from 12.7 to 82.1 µM. Kinetic studies showed that 1 and 5 behave as mixed and non-competitive inhibitors, respectively. Circular dichroism experiments confirmed that 1 and 5 induced conformational changes to hPTP1B1-400. Further insights into the structure of hPTP1B1-400 were obtained from a homology model, which pointed out that the C-terminus (residues 301–400) is highly disordered. Molecular docking with the homologated model suggested that compounds 1 and 3–5 bind to the C-terminal domain, likely inducing conformational changes on the protein. Docking positions of compounds 1, 4, and 5 were refined with molecular dynamics simulations. Importantly, these simulations confirmed the high flexibility of the C-terminus of hPTP1B1-400, as well as the changes to its rigidity when bound to 1, 4, and 5.