Design, identification and validation of novel protein tyrosine phosphatase receptor modulators

Abstract

Protein Tyrosine Phosphatases have a role in metabolism, for this reason, they have been a target of interest in treating obesity and metabolic disorders, however, to date, no successful PTP1B modulators have been produced. PTP1B antagonist DPM-1001 was selected as the lead with evidence of improved insulin sensitivity and obesity states in mice. This study aimed to generate PTP1B modulators including two cohorts of DPM1001 analogs obtained through virtual screening and de novo design. Two pharmacophores, one of DPM-1001 alone, and a consensus pharmacophore obtained via the superimposition of the ligands co-crystallised in PDB crystallographic depositions 2F6V and 2F6T were generated and read into ZincPharmer for virtual screening. De novo design was also carried out. The DPM-1001 molecule was docked into PTP1B, and conformational analysis was done to identify the most stable DPM-1001 conformation. The optimal conformation was used to generate fragments capable of sustaining molecular growth within the PTP1B ligand binding pocket. Virtual screening yielded 1 rule of 3 lead-like hit structure which was docked into a modelled PTP1B protomol for affinity calculation. Sixteen drug-like molecules were generated via de novo design, and the 2 optimal structures were identified. In conclusion, three structures with potential to modulate PTP1B were identified in this study. The lead-like molecule identified through virtual screening although structurally very different from DPM-1001 was able to analogously interact with PTP1B, because it was docked into the receptor protomol. It was noted that in vitro assays would be necessary to determine any actual antagonist activity. The 2 molecules obtained through de novo design bore significant structural similarity to DPM-1001. While in vitro testing is also important in their case, similarity to the lead and molecular growth within the bioactive PTP1B ligand binding pocket increases their propensity for biological activity.