Suggestion of suitable animal models for in vivo studies of protein tyrosine phosphatase 1b (PTP1B) inhibitors using computational approaches.

PTP1B is a prototypic enzyme of the superfamily protein tyrosine phosphatases (PTPs) which are critical regulators of tyrosine phosphorylation-dependent signaling events. It is a highly plausible candidate for designing therapeutic inhibitors of obesity and type 2 diabetes (T2D). In this study, a detailed comparative analysis to reveal the evolutionary relationship of human PTP1B among related vertebrates has been addressed. The phylogenetic trees were constructed with maximum likelihood algorithm by PhyML package on the basis of multiple sequence alignment (MSA) by ClustalΩ and T-coffee. Mutational variability of the sequences corresponding to the 3D structure (pdb: 2vev) was analyzed with Consurf software. The comparative analysis by inhibitor docking to different models was made to confirm the suitability of models. As a result, the PTP1B or PTP non-receptor type 1 homologies show high conservativity where about 70% positions on primary structures are conserved. Within PTP domain (3-277), the most variable positions are 12, 13, 19 and 24 which is a part of the second aryl binding site. Moreover, there are important evolutional mutations that can change the conformation of the proteins, for instance, hydrophilic N139 changed to hydrophobic Gly (mPTP1B); E132 to proline in the hydrophobic core structure or Y46 to cystein in pTyr recognition loop. These variations/differences should be taken into account for rational inhibitor design and in choosing suitable animal models for drug testing and evaluation. Moreover, our study suggests critically potential models which are Heterocephalus glaber, Tupaia chinensis, Sus scrofa, and Rattus norvegicus in addition to the best one Macaca fascicularis. Among these models, the H.glaber and R.norvegicus are preferable over M.musculus thanks to their similarity in binding affinity and binding modes to investigated PTP1B inhibitors.