Development and In silico ADMET Analysis of Novel Flavonoids Derivatives as Potent, Non-Competitive and Selective PTP1B Inhibitors

Abstract

Diabetes mellitus is a serious disease that threatens human health. The most prevalent type of diabetes mellitus is type 2 (T2DM) which is characterized by the lack of insulin secretion and resistance to insulin in target tissues. Protein Tyrosine Phosphatase 1B (PTP1B) plays an important role in the dephosphorylation of phospho-tyrosine residues from the insulin receptor and its substrate. Studies have shown that overexpression of PTP1B protein and its increased activation have been associated with insulin resistance and thus it is a promising therapeutic target for type 2 diabetes. The discovery of selective and effective inhibitors on the active target site present a great challenge due to the site charge and the high degree of conserved active site. Therefore, the identified allosteric site of enzyme PTP1B was chosen to design and evaluate ligands based on effectiveness and selectivity, then filter the compounds based on their ADMET properties in silico to identify the potential inhibitors of the PTP1B enzyme. Among the designed molecules, 14 compounds were obtained with better affinity and selectivity for PTP1B. Some of these compounds showed acceptable pharmacokinetic properties of ADMET and were expected to be non-mutagenic. Thus, they can be considered as promising PTP1B inhibitors.