In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications-A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B.

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

Assessment of Flexible Shape Complementarity: New Opportunities to Explain and Induce Selectivity in Ligands of Protein Tyrosine Phosphatase 1B.

For drug design projects it is essential to rationally induce and explain selectivity. In this context shape complementarity as well as protein and ligand flexibility represent important factors. Currently available tools for the analysis of protein-ligand interactions focus mainly on electrostatic complementarity and/or static structures. Here we address the shortcomings of available methods by presenting two new tools: The first one can be used to assess steric complementarity in flexible protein-ligand complexes in order to explain selectivity of known ligands. It further allows to determine ligand atoms with especially good or bad shape-fit which can be of use in lead optimization projects. The second tool was designed to detect differences in protein flexibility in similar proteins along with their exploitation for virtual screening. Both tools yield interesting results when applied to data of protein tyrosine phosphatase 1B (PTP1B): The case of PTP1B has proven especially difficult in terms of selectivity, due to a closely related phosphatase connected to severe undesired effects. With our tool for steric complementarity assessment we were able to explain previously undisclosed causes of moderate selectivity of selected PTP1B ligands. The second tool allowed us to find differences of flexibility in the two highly similar proteins and give directions for exploitation in virtual screening.