Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors.

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

“…The prevalence of H-bonds in the favored region play a significant role in any ligand-binding analysis because of their strong influence on drug specificity, metabolization and adsorption. It has therefore been used to analyze the potent inhibitors [ 11 , 12 , 55 ].…”

“…The design of the PTP1B inhibitors has been challenging. A number of drug design studies have focused on inhibitors targeting the active site of PTP1B, as it is a conserved region [ 11 , 12 , 13 , 14 ]. The binding of a compound either in an active site or to a secondary noncatalytic region adjacent to the active site is useful to achieve the selectivity for PTP1B [ 15 ].…”

Exploring the antihyperglycemic potential of tetrapeptides devised from AdMc1 via different receptor proteins inhibition using in silico approaches

“… 33 In literature, many proteins have been reported as targets for diabetes including aldose reductase, protein tyrosine phosphatase 1B, α-glucosidase, α-amylase, glycogen synthase kinase 3-beta, DPP-IV and SGLTs. 11 , 17 , 34 , 35 …”

“…Protein tyrosine phosphatase 1B (PTP1B) plays a critical role in multiple cellular signalling pathways more specifically in the insulin signalling and glucose metabolism by dephosphorylation of insulin receptor kinase substrates. 11 The previous studies illustrated that elevated level of PTP1B is the leading cause of many metabolic disorders including DM and obesity. As a negative regulator of insulin signalling pathway, the PTP1B is an attractive pharmacological target for diabetes and obesity.…”

Towards accurate high-throughput ligand affinity prediction by exploiting structural ensembles, docking metrics and ligand similarity

“…Indeed, there are new attempts to combine both, thanks to the increasing number of both atomic structures and affinity measurements. Usually, the combination of LBVS and SBVS is performed in a sequential or parallel manner (Yu et al , 2018; Zhang et al , 2017). The sequential approach uses both methods as filter steps in a hierarchical procedure with increasing refinement.…”